6-cycloamino-3-(pyrid-4-yl)imidazo[1,2-b]pyridazine derivatives, preparation thereof and therapeutic use thereof

ABSTRACT

The invention relates to the 6-cycloamino-3-(pyridin-4-yl)imidazo[I,2-b]pyridazine derivatives corresponding to general formula (I): 
                         
Wherein R 2 , R 3 , R 7 , R 8 , A, L and B are as defined herein. Also disclosed are the preparative methods and therapeutic use thereof.

This application is a divisional application of application U.S. patentapplication Ser. No. 12/647,059, filed Dec. 24, 2009, which is acontinuation of International application No. PCT/FR2008/000,902, filedJun. 26, 2008, which claims the benefit of U.S. Provisional ApplicationNo. 60/946,785, filed Jun. 28, 2007, and the benefit of priority ofFrench patent application Ser. No. 07/04,661, filed Jun. 28, 2007. Thecontents of each of the aforementioned applications are incorporated byreference.

The present invention relates to6-cycloamino-3-(pyrid-4-yl)imidazo[1,2-b]pyridazine derivatives, to aprocess for preparing them and to their therapeutic use, in thetreatment or prevention of diseases involving casein kinase 1 epsilonand/or casein kinase 1 delta.

One subject of the present invention is compounds corresponding to thegeneral formula (I)

in which

-   -   R₂ represents an aryl group optionally substituted with one or        more substituents chosen from halogen atoms and the groups C₁₋₆        alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ fluoroalkyl,        C₁₋₆-fluoroalkyloxy and —CN;    -   R₃ represents a hydrogen atom or a group C₁₋₃ alkyl, —NR₄R₆,        hydroxyl or C₁₋₄ alkyloxy;    -   A represents a group C₁₋₇-alkylene optionally substituted with        one or two groups R_(a);    -   B represents a group C₁₋₇-alkylene optionally substituted with a        group R_(b);    -   L represents either a nitrogen atom optionally substituted with        a group R_(c) or R_(d), or a carbon atom substituted with a        group R_(e1) and a group R_(d) or two groups R_(e2);        the carbon atoms of A and B being optionally substituted with        one or more groups R_(f), which may be identical to or different        than each other;

-   R_(a), R_(b) and R_(c) are defined such that:    -   two groups R_(a) may together form a group C₁₋₆-alkylene;    -   R_(a) and R_(b) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(a) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(b) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;

-   R_(d) represents a group chosen from a hydrogen atom and the groups    C₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl,    C₁₋₆-alkylthio-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,    C₁₋₆-fluoroalkyl, benzyl, C₁₋₆-acyl and hydroxy-C₁₋₆-alkyl;

-   R_(e1) represents a group —NR₄R₅ or a cyclic monoamine optionally    comprising an oxygen atom, the cyclic monoamine being optionally    substituted with one or more substituents chosen from a fluorine    atom and the groups C₁₋₆-alkyl, C₁₋₆-alkyloxy and hydroxyl;

-   two groups R_(e2) form, with the carbon atom that bears them, a    cyclic monoamine optionally comprising an oxygen atom, this cyclic    monoamine being optionally substituted with one or more groups    R_(f), which may be identical to or different than each other;

-   R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    C₁₋₆-alkyloxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or    benzyl;

-   R₄ and R₅ represent, independently of each other, a hydrogen atom or    a group C₁₋₄ alkyl, C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl;    -   R₇ and R₈ represent, independently of each other, a hydrogen        atom or a group C₁₋₆-alkyl.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

In the context of the invention, the following definitions apply:

-   -   C_(t-z) in which t and z may take values from 1 to 7: a        carbon-based chain possibly containing from t to z carbon atoms,        for example C₁₋₇ is a carbon-based chain that may contain from 1        to 7 carbon atoms;    -   alkyl: a linear or branched, saturated aliphatic group; for        example a group C₁₋₆-alkyl represents a linear or branched        carbon-based chain of 1 to 6 carbon atoms, for example a methyl,        ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or        hexyl;    -   alkylene: a linear or branched, saturated divalent alkyl group,        for example a group C₁₋₆-alkylene represents a linear or        branched divalent carbon-based chain of 1 to 6 carbon atoms, for        example a methylene, ethylene, 1-methylethylene or propylene;    -   cycloalkyl: a cyclic alkyl group, for example a group        C₃₋₇-cycloalkyl represents a cyclic carbon-based group of 3 to 7        carbon atoms, for example a cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl or cycloheptyl;    -   acyl: a group alkyl-C(O)—;    -   hydroxyl: a group —OH;    -   cyclic monoamine: a saturated cyclic carbon-based chain        comprising 1 nitrogen atom;    -   hydroxyalkyl: an alkyl group in which a hydrogen atom has been        replaced with a hydroxyl group;    -   alkyloxy: a group —O-alkyl;    -   alkylthio: a group —S-alkyl;    -   fluoroalkyl: an alkyl group in which one or more hydrogen atoms        have been replaced with a fluorine atom;    -   fluoroalkyloxy: an alkyloxy group in which one or more hydrogen        atoms have been replaced with a fluorine atom;    -   a halogen atom: a fluorine, chlorine, bromine or iodine atom;    -   aryl: a monocyclic or bicyclic aromatic group containing between        6 and 10 carbon atoms. Examples of aryl groups that may be        mentioned include phenyl and naphthyl groups.

As nonlimiting examples of cyclic amines or diamines formed by N, A, Land B, mention may be made especially of aziridine, azetidine,pyrrolidine, piperidine, azepine, morpholine, thiomorpholine,homopiperidine, decahydroquinoline, decahydroisoquinoline,azabicycloheptane, azabicyclooctane, azabicyclononane,azaoxobicycloheptane, azathiabicycloheptane, azaoxobicyclooctane,azathiabicyclooctane; piperazine, homopiperazine, diazacyclooctane,diazacyclononane, diazacyclodecane, diazacycloundecane,octahydropyrrolopyrazine, octahydropyrrolodiazepine,octahydropyrrolopyrrole, octahydropyrrolopyridine,decahydronaphthyridine, diazabicycloheptane, diazabicyclooctane,diazabicyclononane, diazaspiroheptane, diazaspirooctane,diazaspirononane, diazaspirodecane, diazaspiroundecane andoxadiazaspiroundecane.

Among the compounds of general formula (I) that are subjects of theinvention, a first group of compounds is constituted by the compoundsfor which R₂ represents a phenyl group optionally substituted with oneor more substituents chosen from halogen atoms and the groups C₁₋₆alkyl, C₁₋₆ alkyloxy and C₁₋₆ fluoroalkyl;

R₃, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a second group of compounds is constituted by the compoundsfor which R₂ represents a phenyl group optionally substituted with oneor more substituents chosen from fluorine and chlorine atoms and methyl,methoxy and trifluoromethyl groups;

R₃, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a third group of compounds is constituted by the compoundsfor which R₃ represents a group chosen from a hydrogen atom and a groupC₁₋₃ alkyl, C₁₋₄ alkyloxy or —NR₄R₅; R₄ and R₅ represent a hydrogen atomor a group C₁₋₄-alkyl;

R₂, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a fourth group of compounds is constituted by the compoundsfor which R₃ represents a group chosen from a hydrogen atom and a methylor methoxy group;

R₂, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a fifth group of compounds is constituted by the compoundsfor which R₃ represents a group chosen from —NH₂, methylamino anddimethylamino;

R₂, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a sixth group of compounds is constituted by the compoundsfor which R₃ represents a group chosen from —NH₂ and dimethylamino;

R₂, A, L, B, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a seventh group of compounds is constituted by the compoundsfor which R₇ and R₈ represent, independently of each other, a hydrogenatom or a methyl group;

R₂, R₃, A, L, B, being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, an eighth group of compounds is constituted by the compoundsfor which:

-   -   A represents a group C₁₋₇-alkylene;    -   B represents a group C₁₋₇-alkylene;    -   L represents a carbon atom substituted with a group R_(e1) and a        group R_(d);    -   R_(d) represents a hydrogen atom;    -   R_(e1) represents a group NR₄R₅, in which R₄ and R₅        independently represent a group C₁₋₄-alkyl; or alternatively        R_(e1) represents a cyclic monoamine optionally comprising an        oxygen atom, the monoamine being optionally substituted with one        or more groups chosen from a fluorine atom and the groups        hydroxyl and C₁₋₆-alkyl;    -   R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a ninth group of compounds is constituted by the compoundsfor which:

-   -   A represents a group —C₂H₄—;    -   B represents a group —C₂H₄— or —CH₂—;    -   L represents a carbon atom substituted with a group R_(e1) and a        group R_(d);    -   R_(d) represents a hydrogen atom;    -   R_(e1) represents a group chosen from the groups dimethylamino,        pyrrolidinyl, morpholinyl, dimethylmorpholinyl,        fluoropyrrolidinyl, hydroxypyrrolidinyl;    -   R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a tenth group of compounds is constituted by the compoundsfor which:

-   -   the cyclic amine formed by —N-A-L-B— represents a        (±)-3-dimethylaminopyrrolidin-1-yl,        4-(pyrrolidin-1-yl)piperid-1-yl, 4-(morpholin-4-yl)piperid-1-yl,        4-(2,6-dimethylmorpholin-4-yl)piperid-1-yl,        4-dimethylaminopiperid-1-yl,        4-((R)-3-fluoropyrrolidin-1-yl)piperid-1-yl or        4-(3-hydroxypyrrolidin-1-yl)piperid-1-yl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, an eleventh group of compounds is constituted by thecompounds for which:

-   -   A represents a group C₁₋₇-alkylene;    -   B represents a group C₁₋₇-alkylene;    -   L represents a carbon atom substituted with a group R_(e1) and a        group R_(d);    -   R_(d) represents a hydrogen atom;    -   R_(e1) represents a group NR₄R₅, in which R₄ and R₅ represent,        independently of each other, a group C₁₋₄-alkyl; or        alternatively R_(e1) represents a cyclic monoamine optionally        comprising an oxygen atom, the monoamine being optionally        substituted with one or more groups chosen from the groups        hydroxyl and C₁₋₆-alkyl;    -   R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a twelfth group of compounds is constituted by the compoundsfor which:

-   -   A represents a group —C₂H₄—;    -   B represents a group —C₂H₄— or —CH₂—;    -   L represents a carbon atom substituted with a group R_(e1) and a        group R_(d);    -   R_(d) represents a hydrogen atom;    -   R_(e1) represents a group chosen from dimethylamino,        pyrrolidinyl, morpholinyl, dimethylmorpholinyl and        hydroxypyrrolidinyl groups;    -   R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a thirteenth group of compounds is constituted by thecompounds for which:

-   -   the cyclic amine formed by —N-A-L-B— represents a        (±)-3-dimethylaminopyrrolidin-1-yl,        (pyrrolidin-1-yl)piperid-1-yl, 4-(morpholin-4-yl)piperid-1-yl,        4-(2,6-dimethylmorpholin-4-yl)-piperid-1-yl,        4-dimethylaminopiperid-1-yl or        4-(3-hydroxypyrrolidin-1-yl)piperid-1-yl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a fourteenth group of compounds is constituted by thecompounds for which:

-   -   A represents a group C₁₋₇-alkylene optionally substituted with        one or two groups R_(a);    -   B represents a group C₁₋₇-alkylene optionally substituted with a        group R_(b);    -   L represents a nitrogen atom optionally substituted with a group        R_(c) or R_(d); the carbon atoms of A and B being optionally        substituted with one or more groups R_(f), which may be        identical to or different than each other;    -   two groups R_(a) may together form a group C₁₋₆-alkylene;    -   R_(a) and R_(b) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(a) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(b) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(d) represents a substituent chosen from a group C₁₋₆-alkyl,        C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl or C₁₋₆-acyl;    -   R_(f) represents a group C₁₋₆-alkyl; hydroxy-C₁₋₆-alkyl or        fluoro-C₁₋₆-alkyl        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a fifteenth group of compounds is constituted by thecompounds for which:

-   -   the cyclic amine formed by —N-A-L-B— represents a piperazinyl, a        diazepanyl, hexahydropyrrolopyrazinyl, diazabicycloheptyl,        octahydropyrrolodiazepinyl, diazabicyclononyl,        hexahydropyrrolopyrrolyl, octahydropyrrolopyridinyl,        decahydronaphthyridinyl or diazaspirodecyl, optionally        substituted with one or more groups chosen from methyl, ethyl,        isopropyl, butyl, cyclopropyl, cyclohexyl, hydroxymethyl,        hydroxyethyl, (hydroxymethyl)propyl, (hydroxymethyl)butyl,        methoxyethyl, fluoromethyl, fluoroethyl, trifluoroethyl, acetyl,        isobutyryl and benzyl groups;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a sixteenth group of compounds is constituted by thecompounds for which:

-   -   the cyclic amine formed by —N-A-L-B— represents a        piperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,        3,3-dimethylpiperazin-1-yl, 3,4-dimethylpiperazin-1-yl,        cis-3,5-dimethylpiperazin-1-yl,        4-(2-hydroxyethyl)piperazin-1-yl,        4-(2-methoxyethyl)piperazin-1-yl,        4-(2-fluoroethyl)piperazin-1-yl,        4-(2,2,2-trifluoroethyl)piperazin-1-yl,        4-cyclopropylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,        4-(2-hydroxy-2-methylpropyl)piperazin-1-yl,        4-n-butylpiperazin-1-yl,        4-(3-hydroxy-3-methylbutyl)piperazin-1-yl,        cyclohexylpiperazin-1-yl, 4-acetylpiperazin-1-yl,        4-isobutyrylpiperazin-1-yl,        (±)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,        1(S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl,        (1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl,        5-isopropyl-2,5-diaza[2.2.1]hept-2-yl,        4-methyl-[1,4]diazepan-1-yl,        (±)-octahydropyrrolo[1,2-d][1,4]diazepin-3-yl,        1,4-diazabicyclo[3.3.2]non-4-yl,        (±)-3,6-diazabicyclo[3.2.0]hept-3-yl,        hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl,        (±)-(cis)-decahydro[2,6]-naphthyridin-2-yl,        3-ethylpiperazin-1-yl, 3,3-diethylpiperazin-1-yl,        3-fluoromethylpiperazin-1-yl, 4-(3-hydroxymethyl)piperazin-1-yl,        3-(1-hydroxy-1-methylethyl)piperazin-1-yl,        3-isopropylpiperazin-1-yl,        (1R,5R)-3,6-diazabicyclo[3.2.0]hept-2-yl,        5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl,        1-((1S,4S)-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpropan-2-ol,        3,6-diazabicyclo[3.1.1]hept-3-yl,        5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (±)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (+)-hexahydropyrrolo[3,4-b]pyrrol-5(1H-yl,        (−)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl or        6,9-diazaspiro[4.5]dec-9-yl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a seventeenth group of compounds is constituted by thecompounds for which:

-   -   A represents a group C₁₋₇-alkylene optionally substituted with        one or two groups R_(a);    -   B represents a group C₁₋₇-alkylene optionally substituted with a        group R_(b);    -   L represents a nitrogen atom optionally substituted with a group        R_(c) or R_(d); the carbon atoms of A and B being optionally        substituted with one or more identical or different groups        R_(f);    -   R_(a) and R_(b) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(a) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(b) and R_(c) may together form a bond or a group        C₁₋₆-alkylene;    -   R_(d) represents a substituent chosen from the groups        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl,        benzyl and C₁₋₆-acyl;    -   R_(f) represents a group C₁₋₆-alkyl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, an eighteenth group of compounds is constituted by thecompounds for which:

-   -   the cyclic amine formed by —N-A-L-B— represents a piperazinyl, a        diazepanyl, hexahydropyrrolopyrazinyl, diazabicycloheptyl,        octahydropyrrolodiazepinyl, diazabicyclononyl,        hexahydropyrrolopyrrolyl, octahydropyrrolopyridinyl or        decahydronaphthyridinyl, optionally substituted with one or more        groups chosen from methyl, ethyl, isopropyl, butyl, cyclopropyl,        cyclohexyl, hydroxyethyl, (hydroxymethyl)propyl,        (hydroxymethyl)butyl, methoxyethyl, fluoroethyl, trifluoroethyl,        acetyl, isobutyryl and benzyl groups;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a nineteenth group of compounds is constituted by thecompounds for which:

-   -   the cyclic amine formed by —N-A-L-B— represents a        piperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,        3,3-dimethylpiperazin1-yl, 3,4-dimethylpiperazin-1-yl,        cis-3,5-dimethylpiperazin-1-yl,        4-(2-hydroxyethyl)piperazin-1-yl,        4-(2-methoxyethyl)piperazin-1-yl,        4-(2-fluoroethyl)piperazin-1-yl,        4-(2,2,2-trifluoroethyl)piperazin-1-yl,        4-cyclopropylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,        4-(2-hydroxy-2-methylpropyl)piperazin-1-yl,        4-n-butylpiperazin-1-yl,        4-(3-hydroxy-3-methylbutyl)piperazin-1-yl,        cyclohexylpiperazin-1-yl, 4-acetylpiperazin-1-yl,        4-isobutyrylpiperazin-1-yl,        (±)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (S)-hexahydropyrrolo[1,3-a]pyrazin-2-yl,        (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,        1(S,4S)-5-benzyl-2,5-diazabicyclo-[2.2.1]hept-2-yl,        (1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl,        5-isopropyl-2,5-diaza[2.2.1]hept-2-yl,        4-methyl[1,4]diazepan-1-yl,        (±)-octahydropyrrolo[1,2-d][1,4]diazepin-3-yl,        1,4-diazabicyclo[3.3.2]non-4-yl,        (±)-3,6-diazabicyclo[3.2.0]hept-3-yl,        hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-benzylhexahydropyrrolo[3,4-c]-pyrrol-2(1H)-yl,        5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl or        (±)-(cis)-decahydro-[2,6]naphthyridin-2-yl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a twentieth group of compounds is constituted by thecompounds for which:

-   -   A represents a group C₁₋₇-alkylene;    -   B represents a group C₁₋₇-alkylene;    -   L represents a carbon atom substituted with two groups R_(e2);        the carbon atoms of A and B being optionally substituted with        one or more groups R_(f), which may be identical to or different        than each other;    -   two groups R_(e2) form, with the carbon atom that bears them, a        pyrrolidine, piperidine or morpholine group;    -   R_(f) represents a group C₁₋₆-alkyl;        R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-first group of compounds is constituted by thecompounds for which:

the cyclic amine formed by —N-A-L-B— represents a diazaspirononyl,diazaspirodecyl, diazaspiroundecyl or oxadiazaspiroundecyl;

R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-second group of compounds is constituted by thecompounds for which:

the cyclic amine formed by —N-A-L-B— represents a(±)-2,7-diazaspiro[4.4]non-2-yl, (±)-2,8-diazaspiro[4.5]dec-2-yl,(±)-2,7-diazaspiro[4.5]dec-2-yl, (±)-2,8-diazaspiro[4.5]dec-8-yl,(±)-2,7-diazaspiro[4.5]dec-7-yl, 3,9-diazaspiro[5.5]undec-3-yl,2,9-diazaspiro[5.5]undec-9-yl, (±)-2,8-diazaspiro[5.5]undec-2-yl or1-oxa-4,9-diazaspiro[5.5]undec-9-yl;R₂, R₃, R₇ and R₈ being as defined above.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-third group of compounds is constituted by thecompounds for which:

-   -   R₂ represents a phenyl group optionally substituted with one or        more substituents chosen from fluorine and chlorine atoms and a        methyl group;    -   R₃ represents a hydrogen atom;    -   the cyclic amine formed by —N-A-L-B— represents a        (±)-3-dimethylaminopyrrolidin-1-yl,        4-(pyrrolidin-1-yl)piperid-1-yl, 4-(morpholin-4-yl)piperid-1-yl,        4-(2,6-dimethylmorpholin-4-yl)piperid-1-yl,        4-dimethylaminopiperid-1-yl,        4-(3-hydroxypyrrolidin-1-yl)piperid-1-yl or        4-(3-fluoropyrrolidin-1-yl)piperid-1-yl;    -   R₇ and R₈ represent a hydrogen atom.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-fourth group of compounds is constituted by thecompounds for which:

-   -   R₂ represents a phenyl group optionally substituted with one or        more substituents chosen from fluorine and chlorine atoms and        methyl, methoxy and trifluoromethyl groups;    -   R₃ represents a hydrogen atom or a methyl, methoxy, —NH₂,        methylamino, or dimethylamino group;    -   the cyclic amine formed by —N-A-L-B— represents a        piperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,        3,3-dimethylpiperazin1-yl, 3,4-dimethylpiperazin-1-yl,        cis-3,5-dimethylpiperazin-1-yl,        4-(2-hydroxyethyl)piperazin-1-yl,        4-(2-methoxyethyl)piperazin-1-yl,        4-(2-fluoroethyl)piperazin-1-yl,        4-(2,2,2-trifluoroethyl)piperazin-1-yl,        4-cyclopropylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,        4-(2-hydroxy-2-methylpropyl)piperazin-1-yl,        4-n-butylpiperazin-1-yl,        4-(3-hydroxy-3-methylbutyl)piperazin-1-yl,        cyclohexylpiperazin-1-yl, 4-acetylpiperazin-1-yl,        4-isobutyrylpiperazin-1-yl,        (±)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,        1(S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl,        (1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl,        5-isopropyl-2,5-diaza[2.2.1]hept-2-yl,        4-methyl-[1,4]diazepan-1-yl,        (±)-octahydropyrrolo[1,2-d][1,4]diazepin-3-yl,        1,4-diazabicyclo[3.3.2]non-4-yl,        (±)-3,6-diazabicyclo[3.2.0]hept-3-yl,        hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl,        (±)-(cis)-decahydro[2,6]-naphthyridin-2-yl,        3-ethylpiperazin-1-yl, 3,3-diethylpiperazin-1-yl,        3-fluoromethylpiperazin-1-yl, 4-(3-hydroxymethyl)piperazin-1-yl,        3-(1-hydroxy-1-methylethyl)piperazin-1-yl,        3-isopropylpiperazin-1-yl,        (1R,5R)-3,6-diazabicyclo[3.2.0]hept-2-yl,        5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl,        1-((1S,4S)-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpropan-2-ol,        3,6-diazabicyclo[3.1.1]hept-3-yl,        5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (±)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (+)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (−)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl or        6,9-diazaspiro[4.5]dec-9-yl;    -   R₇ and R₈ independently represent a hydrogen atom or a methyl        group.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-fifth group of compounds is constituted by thecompounds for which:

-   -   R₂ represents a phenyl group optionally substituted with one or        more substituents chosen from fluorine and chlorine atoms;    -   R₃ represents a hydrogen atom;    -   the cyclic amine formed by —N-A-L-B— represents a        (±)-3-dimethylaminopyrrolidin-1-yl,        4-(pyrrolidin-1-yl)piperid-1-yl, 4-(morpholin-4-yl)piperid-1-yl,        4-(2,6-dimethylmorpholin-4-yl)piperid-1-yl,        4-dimethylaminopiperid-1-yl or        4-(3-hydroxypyrrolidin-1-yl)piperid-1-yl;    -   R₇ and R₈ represent a hydrogen atom.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-sixth group of compounds is constituted by thecompounds for which:

-   -   R₂ represents a phenyl group optionally substituted with one or        more substituents chosen from fluorine and chlorine atoms and        methyl, methoxy and trifluoromethyl groups;    -   R₃ represents a hydrogen atom or a methyl, methoxy, —NH₂ or        dimethylamino group;    -   the cyclic amine formed by —N-A-L-B— represents a        piperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,        3,3-dimethylpiperazin1-yl, 3,4-dimethylpiperazin-1-yl,        cis-3,5-dimethylpiperazin-1-yl,        4-(2-hydroxyethyl)piperazin-1-yl,        4-(2-methoxyethyl)piperazin-1-yl,        4-(2-fluoroethyl)piperazin-1-yl,        4-(2,2,2-trifluoroethyl)piperazin-1-yl,        4-cyclopropylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,        4-(2-hydroxy-2-methylpropyl)piperazin-1-yl,        4-n-butylpiperazin-1-yl,        4-(3-hydroxy-3-methylbutyl)piperazin-1-yl,        4-cyclohexylpiperazin-1-yl, 4-acetylpiperazin-1-yl,        4-isobutyrylpiperazin-1-yl,        (±)-3,6-diazabicyclo[3.2.0]hept-3-yl,        (±)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,        (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,        (1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl,        5-isopropyl-2,5-diaza[2.2.1]hept-2-yl,        4-methyl[1,4]diazepan-1-yl,        (±)-octahydropyrrolo[1,2-d][1,4]diazepin-2-yl,        1,4-diazabicyclo-[3.3.2]non-4-yl,        hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-2(1H-yl,        5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        5-cyclopropylhexahydropyrrolo[3,4-c]-pyrrol-2(1H)-yl,        5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl or        (±)-(cis)-decahydro[2,6]naphthyridin-2-yl;    -   R₇ and R₈ represent, independently of each other, a hydrogen        atom or a methyl group.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-seventh group of compounds is constituted by thecompounds for which:

-   -   R₂ represents a phenyl group optionally substituted with one or        more substituents chosen from fluorine and chlorine atoms;    -   R₃ represents a hydrogen atom or a methyl, methoxy or —NH₂        group;    -   the cyclic amine formed by —N-A-L-B— represents        (±)-2,7-diazaspiro[4.4]non-2-yl,        (±)-2,8-diazaspiro[4.5]dec-2-yl,        (±)-2,7-diazaspiro[4.5]dec-2-yl,        (±)-2,8-diazaspiro[4.5]dec-8-yl,        (±)-2,7-diazaspiro[4.5]dec-7-yl, 3,9-diazaspiro[5.5]undec-3-yl,        2,9-diazaspiro[5.5]undec-9-yl, (±)-2,8-diazaspiro[4.5]undec-2-yl        or 1-oxa-4,9-diazaspiro[5.5]undec-9-yl;    -   R₇ and R₈ represent a hydrogen atom.

Among the compounds of general formula (I) that are subjects of theinvention, mention may be made especially of the following compounds:

-   2-Phenyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-7,8-dimethyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   4-[2-(4-Fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;-   2-(4-Chlorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Chlorophenyl)-7-methyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Chlorophenyl)-8-methyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dimethylphenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Difluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Difluorophenyl)-3-(2-methylpyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;-   2-(3,4-Difluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dichlorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dichlorophenyl)-3-(2-methylpyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;-   (±)-6-(3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((R)-3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((R)-3-Methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;-   6-((S)-3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Fluorophenyl)-6-(R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(S)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-(2-methoxpyrid-4-yl)-6-(R)-3-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine;-   2-(3,4-Difluorophenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   4-[2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   4-[2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   2-(3,5-Dichlorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dichlorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   (±)-6-(3,4-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((cis)-3,5-Dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;-   6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((cis)3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(3,5-Dimethylphenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,4-Difluorophenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Chlorophenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(2-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,4-Difluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Methoxyphenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Methoxyphenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(4-Methylpiperazin-1-yl)-3-pyrid-4-yl-2-p-tolylimidazo[1,2-b]pyridazine;-   6-(4-Methylpiperazin-1-yl)-3-pyrid-4-yl-2-(4-trifluoromethylphenyl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   {4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-ypimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}-dimethylamine;-   2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine;-   6-(4-Ethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3,5-Dimethylphenyl)-6-(4-ethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-[4-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl]ethanol;-   2-{4-[2-(3-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[2-(3,4-Difluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[2-(4-Chlorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[3-(2-Aminopyrid-4-yl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-(4-Chlorophenyl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-[4-(2-Fluoroethyl)piperazin-1-yl]-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-[4-(2-Fluoroethyl)piperazin-1-yl]-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-Phenyl-3-pyrid-4-yl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-pyrid-4-yl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]imidazo[1,2-b]pyridazine;-   6-(4-Cyclopropylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(4-Cyclopropylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   6-(4-Isopropylpiperazin-1-yl)-3-(2-methoxpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;-   2-(3-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(3,4-Difluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   4-[2-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   2-Methyl-1-[4-(2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl]propan-2-ol;-   1-{4-[2-(3-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   1-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   6-(4-Butylpiperazin-1-yl)-2-(4-chlorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   4-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylbutan-2-ol;-   6-(4-Cyclohexylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   1-{-4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanone;-   1-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-1-one;-   (±)-2-(4-Fluorophenyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl-3-(2-methoxypyrid-4-yl)-imidazo[1,2-b]pyridazine;-   6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-{(1S,4S)-5-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethanol;-   2-(4-Fluorophenyl)-6-(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-methyl[1,4]diazepan-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-3-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]octahydro(1H)pyrrolo[1,2-d][1,4]diazepine;-   (±)-4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-1,4-diazabicyclo[3.2.2]nonane;-   (±)-4-[2-(3,5-Dimethylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-1,4-diazabicyclo[3.2.2]nonane;-   (±)-3,6-diazabicyclo[3.2.0]hept-3-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;-   6-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;-   2-(3-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   4-[2-(4-Chlorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methoxypyrid-4-yl)-imidazo[1,2-b]pyridazine;-   4-[6-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7,8-dimethyl-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   4-[2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   6-(5-Cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2-(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methoxpyrid-4-yl)imidazo[1,2-b]pyridazine-   (±)-6-(Octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-3-(2-Methylpyrid-4-yl)-6-(octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl)-2-phenylimidazo[1,2-b]pyridazine;-   (±)-(cis)-2-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]decahydro[2,6]-naphthyridine;-   (±)-6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(2,8-Diazaspiro[4.5]dec-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(2,7-Diazaspiro[4.5]dec-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(2,8-Diazaspiro[4.5]dec-8-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(2,7-Diazaspiro[4.5]dec-7-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   3-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-3,9-diazaspiro[5.5]undecane;-   9-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)-2,9-diazaspiro[5.5]undecane;-   9-[3-(2-Methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;-   9-[2-(3-Fluorophenyl)-3-(2-methylpyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]-undecane;-   9-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;-   9-[2-(4-Fluorophenyl)-3-(2-methylpyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]-undecane;-   4-[2-(4-Chlorophenyl)-6-(2,9-diazaspiro[5.5]undec-9-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;-   9-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro-[5.5]undecane;-   2-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane-   2-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,8-diazaspiro[5.5]undecane-   9-[2-(phenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-0]-1-oxa-4,9-diazaspiro[5.5]undecane;-   9-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]-undecane;-   9-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane;-   4-{[2-(4-Chlorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-2-ylamine;-   (±)-{1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl}dimethylamine;-   2-(3,5-Dimethylphenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;-   6-(4-Morpholin-4-ylpiperid-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-[4-(2,6-Dimethylmorpholin-4-yl)piperid-1-yl]-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperid-4-yl}dimethylamine;-   2-Phenyl-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;-   (R)-1-{1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperid-4-yl}pyrrolidin-3-ol;-   6-(4-Morpholin-4-ylpiperid-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Fluoro-5-methylphenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {-4-[2-(4-Fluorophenyl)-6-((R)-3-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Dimethylpiperazin-1-yl)-2-(3-fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {4-[6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   6-((R)-3-Ethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(3,3-Diethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(3-Fluoromethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-2-yl}methanol;-   2-{4-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   2-{4-[2-(4-Fluorophenyl)-3-(2-methylaminopyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;-   1-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   1-{4-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   1-{4-[2-(4-Fluorophenyl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   1-{4-[2-(4-Fluorophenyl)-3-(2-methylaminopyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;-   2-{(R)-4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-2-yl}propan-2-ol;-   2-(4-Fluorophenyl)-6-((R)-3-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-6-((R)-3-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   2-(3-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   2-(3,4-Difluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(3-Fluoro-5-methylphenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-6-(3,6-Diazabicyclo[3.2.0]hept-3-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   {4-[(1S,4S)-6-2,5-Diazabicyclo[2.2.1]hept-2-yl-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-7-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-8-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   2-Methyl-1-[(1S,4S)-5-(2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]propan-2-ol;-   6-(3,6-Diazabicyclo[3.1.1]hept-3-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-7-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-8-methyl-6-(−5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-8-methyl-6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   {4-[2-(4-Fluorophenyl)-7-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   (±)-2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (+)-2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (−)-2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-{4-[2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   3-(2-Methylpyrid-4-yl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenylimidazo[1,2-b]pyridazine;-   3-(2-Methylpyrid-4-yl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-8-methyl-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-7-methyl-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-7-methyl-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-(2-methylpyrid-4-yl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-ylimidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-6-(octahydropyrrolo[3,4-b]pyrid-6-ylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   6-(4aR,7aR)-Octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-3-(2-methylpyrid-4-yl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-ylimidazo[1,2-b]pyridazine;-   2-(4-Fluorophenyl)-8-methyl-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (±)-2-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,8-diazaspiro[5.5]undecane;-   9-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;-   {4-[6-(2,9-Diazaspiro[5.5]undec-9-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   9-[2-(3,4-Difluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;-   9-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;-   2-(3-Fluorophenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;-   {4-[2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;-   2-(4-Fluorophenyl)-6-[4-((R)-3-fluoropyrrolidin-1-yl)piperid-1-yl]-3-pyrid-4-ylimidazo[1,2-b]pyridazine;-   (R)-1-[1-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperid-4-yl]pyrrolidin-3-ol;-   (R)-1-{1-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperid-4-yl}-pyrrolidin-3-ol.

Table 1 below illustrates the chemical structures and the physicalproperties of a number of compounds according to the invention.

In this table:

-   -   the “m.p. ° C.” column gives the melting points of the products        in degrees Celsius. “N.D” means that the melting point is not        determined,    -   in the “m.p. ° C.” column, “HCl” or “CF₃COOH” represents a        compound in hydrochloride or trifluoroacetate form and the ratio        in parentheses is the (acid:base) ratio,    -   the “LC-MS or (MS)” column gives the results of analysis of the        products by LC-MS (liquid chromatography coupled to mass        spectroscopy) performed on an Agilent LC-MSD Trap machine in        positive ESI mode or by MS (mass spectroscopy) on an Autospec M        machine (EBE) using the DCI-NH₃ technique.    -   “decomp” means that the compound undergoes decomposition;    -   “Me-amino” means methylamino;    -   “Me” means methyl;    -   “MeO” means methoxy;

TABLE 1 N° —N—A—L—B— R₇ R₈ R₂ R₃ m.p. ° C. M + H 1 Piperazin-1-yl H HPhenyl H N.D 357 2 Piperazin-1-yl H H 4-Fluorophenyl H 240-242 375 3Piperazin-1-yl Me Me 4-Fluorophenyl H 233-235 403 4 Piperazin-1-yl H H4-Fluorophenyl Amino 255 decomp. 390 5 Piperazin-1-yl H H 4-FluorophenylMeO 227-229 405 6 Piperazin-1-yl H H 4-Chlorophenyl H 238-240 391 7Piperazin-1-yl Me H 4-Chlorophenyl H 180-182 405 8 Piperazin-1-yl H Me4-Chlorophenyl H 216-218 405 9 Piperazin-1-yl H H 3,5-Dimethylphenyl HN.D. 385 10 Piperazin-1-yl H H 3,5-Difluorophenyl H N.D 393 11Piperazin-1-yl H H 3,5-Difluorophenyl Me N.D 407 12 Piperazin-1-yl H H3,4-Difluorophenyl H 183-185 393 13 Piperazin-1-yl H H3,5-Dichlorophenyl H N.D 425 14 Piperazin-1-yl H H 3,5-Dichlorophenyl MeN.D 439 15 (±)-3-Methylpiperazin-1-yl H H Phenyl H N.D 371 16(R)-3-Methylpiperazin-1-yl H H Phenyl H N.D 371 17(R)-3-Methylpiperazin-1-yl H H Phenyl Me N.D 385 18(S)-3-Methylpiperazin-1-yl H H Phenyl H N.D 371 19(R)-3-Methylpiperazin-1-yl H H 3-Fluorophenyl H N.D 389 20(±)-3-Methylpiperazin-1-yl H H 4-Fluorophenyl H 197-199 389 21(R)-3-Methylpiperazin-1-yl H H 4-Fluorophenyl H N.D 389 22(S)-3-Methylpiperazin-1-yl H H 4-Fluorophenyl H N.D 389 23(R)-3-Methylpiperazin-1-yl H H 4-Fluorophenyl MeO 215-218 419 24(R)-3-Methylpiperazin-1-yl H H 3,4-Difluorophenyl H N.D 407 253,3-Dimethylpiperazin-1-yl H H Phenyl H N.D 385 263,3-Dimethylpiperazin-1-yl H H 4-Fluorophenyl H 232-235 403 HCl (3:1) 273,3-Dimethylpiperazin-1-yl H H 4-Fluorophenyl MeO 167-170 433 283,3-Dimethylpiperazin-1-yl H H 3,5-Dimethylphenyl H N.D 413 293,3-Dimethylpiperazin-1-yl H H 3,5-Dimethylphenyl Me N.D 427 303,3-Dimethylpiperazin-1-yl H H 3,5-Dimethylphenyl Amino N.D 428 313,3-Dimethylpiperazin-1-yl H H 3,5-Difluorophenyl H N.D 421 323,3-Dimethylpiperazin-1-yl H H 3,5-Difluorophenyl Me N.D 435 333,3-Dimethylpiperazin-1-yl H H 3,5-Difluorophenyl Amino N.D 436 343,3-Dimethylpiperazin-1-yl H H 3,5-Dichlorophenyl H N.D 453 353,3-Dimethylpiperazin-1-yl H H 3,5-Dichlorophenyl Me N.D 467 36(±)-3,4-Dimethylpiperazin-1-yl H H 4-Fluorophenyl H 254-256 403 37cis-3,5-Dimethylpiperazin-1-yl H H Phenyl H N.D 385 38cis-3,5-Dimethylpiperazin-1-yl H H Phenyl Me N.D 399 39cis-3,5-Dimethylpiperazin-1-yl H H 3-Fluorophenyl H N.D 403 40cis-3,5-Dimethylpiperazin-1-yl H H 4-Fluorophenyl H 231-233 403 41cis-3,5-Dimethylpiperazin-1-yl H H 4-Fluorophenyl MeO 173-175 433 42cis-3,5-Dimethylpiperazin-1-yl H H 3,5-Dimethylphenyl H N.D 413 43cis-3,5-Dimethylpiperazin-1-yl H H 3,4-Difluorophenyl H N.D 421 44cis-3,5-Dimethylpiperazin-1-yl Me H 4-Chlorophenyl H 230-232 433 45cis-3,5-Dimethylpiperazin-1-yl H Me 4-Fluorophenyl H 235-237 417 464-Methylpiperazin-1-yl H H 2-Chlorophenyl H 198-200 405 474-Methylpiperazin-1-yl H H 3-Chlorophenyl H 195-197 405 484-Methylpiperazin-1-yl H H 4-Chlorophenyl H 260-262 405 494-Methylpiperazin-1-yl H H 3-Fluorophenyl H 205-206 389 504-Methylpiperazin-1-yl H H 4-Fluorophenyl H 294-296 389 248-250 514-Methylpiperazin-1-yl H H 3,4-Difluorophenyl H 210 407 524-Methylpiperazin-1-yl H H 3-Methoxyphenyl H 131 401 534-Methylpiperazin-1-yl H H 4-Methoxyphenyl H 183-185 401 544-Methylpiperazin-1-yl H H 4-Methylphenyl H 205-206 385 554-Methylpiperazin-1-yl H H 4-Trifluoromethyl-phenyl H 201-203 439 564-Methylpiperazin-1-yl H H 4-Fluorophenyl Me 258-260 403 574-Methylpiperazin-1-yl H H 4-Fluorophenyl Amino 235-238 404 584-Methylpiperazin-1-yl H H 4-Fluorophenyl Di-Me-amino 180-183 432 594-Methylpiperazin-1-yl H H 4-Fluorophenyl MeO 189-194 419 604-Ethylpiperazin-1-yl H H 4-Fluorophenyl H 208-210 403 614-Ethylpiperazin-1-yl H H 3,5-Dimethylphenyl H N.D 413 624-(2-hydroxyethyl)piperazin-1-yl H H Phenyl H N.D 401 634-(2-hydroxyethyl)piperazin-1-yl H H 3-Fluorophenyl H N.D 419 644-(2-hydroxyethyl)piperazin-1-yl H H 4-Fluorophenyl H 203-206 419 654-(2-hydroxyethyl)piperazin-1-yl H H 4-Fluorophenyl MeO 176-179 449 664-(2-hydroxyethyl)piperazin-1-yl H H 3,4-Difluorophenyl H N.D 437 674-(2-hydroxyethyl)piperazin-1-yl H H 4-Chlorophenyl H N.D 435 684-(2-hydroxyethyl)piperazin-1-yl H H 4-Chlorophenyl amino 191-193 450 694-(2-Methoxyethyl)piperazin-1-yl H H 4-Chlorophenyl H N.D 449 704-(2-Fluoroethyl)piperazin-1-yl H H 4-Fluorophenyl H 183-185 421 714-(2-Fluoroethyl)piperazin-1-yl H H 4-Fluorophenyl MeO 149-151 451 724-(2,2,2-Trifluoroethyl)piperazin-1-yl H H Phenyl H 188-190 439 734-(2,2,2-Trifluoroethyl)piperazin-1-yl H H 4-Fluorophenyl H 188-191 457184-186 74 4-Cyclopropylpiperazin-1-yl H H 4-Fluorophenyl H 205-208 41575 4-Cyclopropylpiperazin-1-yl H H 4-Fluorophenyl MeO 194-196 445 764-Isopropylpiperazin-1-yl H H Phenyl MeO 157-159 429 774-Isopropylpiperazin-1-yl H H 3-Fluorophenyl H N.D 417 784-Isopropylpiperazin-1-yl H H 4-Fluorophenyl H 185-187 417 794-Isopropylpiperazin-1-yl H H 4-Fluorophenyl MeO 153-156 447 804-Isopropylpiperazin-1-yl H H 3,4-Difluorophenyl H N.D 435 814-Isopropylpiperazin-1-yl H H 4-Chlorophenyl amino 236-239 448 824-(2-Hydroxy-2-methylpropyl)piperazin-1-yl H H Phenyl H N.D 429 834-(2-Hydroxy-2-methylpropyl)piperazin-1-yl H H 3-Fluorophenyl H N.D 44784 4-(2-Hydroxy-2-methylpropyl)piperazin-1-yl H H 4-Fluorophenyl MeO176-178 477 85 4-n-Butylpiperazin-1-yl H H 4-Chlorophenyl H N.D 447 864-(3-Hydroxy-3-methylbutyl)piperazin-1-yl H H 4-Fluorophenyl MeO 151-154491 87 4-Cyclohexylpiperazin-1-yl H H 4-Fluorophenyl H 197-199 457 884-Acetylpiperazin-1-yl H H 4-Fluorophenyl H 231-233 417 894-Isobutyrylpiperazin-1-yl H H 4-Fluorophenyl H 197-200 445 90(±)-Hexahydropyrrolo[1,2-a]pyrazin-2-yl  

H H 4-Fluorophenyl H 223-225 415 91(S)-Hexahydropyrrolo[1,2-a]pyrazin-2-yl  

H H 4-Fluorophenyl MeO 187-189 445 92(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl  

H H Phenyl H N.D 369 93(1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl H H 3-Fluorophenyl HN.D 477 94 (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl H H 4-Fluorophenyl H192-196 387 95 (1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl H H4-Fluorophenyl H 182-184 477 96 (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylH H 4-Fluorophenyl MeO 164-167 417 97(1S,4S)-5-(2-Hydroxyethyl)-2,5-diaza-bicyclo H H 4-Fluorophenyl MeO154-156 461 [2.2.1]hept-2-yl 985-Isopropyl-2,5-diazabicyclo[2.2.1]-hept-2-yl H H 4-Fluorophenyl MeO204-206 459 99 4-Methyl[1,4]diazepan-1-yl H H 4-Fluorophenyl H 138-140403 100 (±)-Octahydro-1H-pyrrolo[1,2-d][1,4]-diazepin-3-yl  

H H 4-Fluorophenyl H 166-168 429 101 (±)-1,4-Diazabicyclo[3.2.2]non-4-yl 

H H 4-Fluorophenyl H 286-288 415 102 (±)-1,4-Diazabicyclo[3.2.2]non-4-ylH H 3,5-Dimethyl-phenyl H N.D 425 103(±)-3,6-diazabicyclo[3.2.0]hept-3-yl  

H H Phenyl H 212-218 370 104 (±)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl 

H H Phenyl H 181-183 383 105 Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl H HPhenyl Me 170-172 397 106 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl  

H H Phenyl H 199-201 383 107 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H HPhenyl Me 214-217 397 108 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H3-Fluorophenyl Me 217-219 415 109 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylH H 4-Fluorophenyl H 246-250 401 195-198 110Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H 4-Fluorophenyl Me 200-202 415111 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H 4-Chlorophenyl Amino267-270 432 112 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H4-Fluorophenyl MeO 126-129 431 1135-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl Me Me 4-FluorophenylAmino 113 114 Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl Me Me4-Fluorophenyl Amino 254-256 444 1155-Cyclopropylhexahydropyrrolo[3,4-c] H H 4-Fluorophenyl H 204-206 441pyrrol-2(1H)-yl 116 5-Isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl HH 4-Fluorophenyl H 200-202 443 1175-Isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H 4-Fluorophenyl Me197-199 457 118 5-Isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl H H4-Fluorophenyl MeO 208-211 473 119(±)-(cis)-Octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl  

H H Phenyl H 212-215 397 120(±)-(cis)-Octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl H H Phenyl Me 208-210411 121 (±)-(cis)-Decahydro[2,6]naphthyridin-2-yl  

H H 4-Fluorophenyl H 231-234 (3HCl) 429 122(±)-2,7-Diazaspiro[4.4]non-2-yl  

H H 3-Fluorophenyl H N.D 415 123 (±)-2,7-Diazaspiro[4.4]non-2-yl H H4-Fluorophenyl H 204-206 415 124 (±)-2,8-Diazaspiro[4.5]dec-2-yl  

H H 4-Fluorophenyl H 198-200 429 125 (±)-2,7-Diazaspiro[4.5]dec-2-yl  

H H 4-Fluorophenyl H 228-230 429 126 (±)-2,8-Diazaspiro[4.5]dec-8-yl  

H H 4-Fluorophenyl H 223-225 429 127 (±)-2,7-Diazaspiro[4.5]dec-7-yl  

H H 4-Fluorophenyl H 162-165 429 128 3,9-Diazaspiro[5.5]dec-3-yl  

H H 4-Fluorophenyl H 230-232 443 129 2,9-Diazaspiro[5.5]undec-9-yl  

H H Phenyl H 173-176 425 130 2,9-Diazaspiro[5.5]undec-9-yl H H Phenyl Me175-179 439 131 2,9-Diazaspiro[5.5]undec-9-yl H H 3-Fluorophenyl Me189-191 457 132 2,9-Diazaspiro[5.5]undec-9-yl H H 4-Fluorophenyl H253-255 443 133 2,9-Diazaspiro[5.5]undec-9-yl H H 4-Fluorophenyl Me228-230 457 134 2,9-Diazaspiro[5.5]undec-9-yl H H 4-Chlorophenyl Amino255-258 474 240-243 135 2,9-Diazaspiro[5.5]undec-9-yl H H 4-FluorophenylMeO 191-194 473 136 2,9-Diazaspiro[5.5]undec-9-yl  

H H 4-Fluorophenyl H 248-250 443 137 (±)-2,8-Diazaspiro[5.5]undec-9-yl  

H H 4-Fluorophenyl H 218-220 443 138 1-Oxa-4,9-diazaspiro[5.5]undec-9-yl 

H H Phenyl H N.D. 427 139 1-Oxa-4,9-diazaspiro[5.5]undec-9-yl H H4-Fluorophenyl H 219-221 445 140 1-Oxa-4,9-diazaspiro[5.5]undec-9-yl H H4-Fluorophenyl MeO 198-200 475 141 1-Oxa-4,9-diazaspiro[5.5]undec-9-yl HH 4-Chlorophenyl amino 241-244 476 142(±)-3-Dimethylaminopyrrolidin-1-yl H H 4-Fluorophenyl H 184-186 403 1434-(Pyrrolidin-1-yl)piperid-1-yl H H 3,5-Dimethyl-phenyl H N.D. 453 1444-(Morpholin-4-yl)piperid-1-yl H H Phenyl H N.D. 441 1454-(2,6-Dimethylmorpholin-4-yl)-piperid-1-yl H H Phenyl H N.D. 469 1464-Dimethylaminopiperid-1-yl H H 4-Fluorophenyl H 193-195 417 1474-Pyrrolidin-1-ylpiperid-1-yl H H Phenyl H 165.0-165.5 425 1484-Pyrrolidin-1-ylpiperid-1-yl H H 4-Fluorophenyl H 210-212 443 1494-Pyrrolidin-1-ylpiperid-1-yl H H 4-Fluorophenyl MeO 161-164 473 1504-((R)-3-Hydroxypyrrolidin-1-yl)-piperid-1-yl H H 4-Fluorophenyl H203-205 459 151 4-Morpholin-4-ylpiperid-1-yl H H Phenyl H N.D. 441 152(R)-3-Methyl-piperazin-1-yl H H 3-Fluoro-5-methyl-phenyl H 216-219 403153 (R)-3-Methyl-piperazin-1-yl H H 4-Fluoro-phenyl Me-amino 232-234 418154 3,3-Dimethyl-piperazin-1-yl Me H 4-Fluoro-phenyl H 224-226 417 1553,3-Dimethyl-piperazin-1-yl H Me 4-Fluoro-phenyl H 224-226 417 222-224156 3,3-Dimethyl-piperazin-1-yl H H 3-Fluoro-5-methyl-phenyl H 218-221417 157 3,3-Dimethyl-piperazin-1-yl H H 4-Fluoro-phenyl Me-amino 235-237432 158 (R)-3-Ethyl-piperazin-1-yl H H 4-Fluoro-phenyl H 186-188 403 1593,3-Diethyl-piperazin-1-yl H H 4-Fluoro-phenyl H  82-184 431 160(±)-3-Fluoromethyl-piperazin-1-yl H H 4-Fluoro-phenyl H 198-200 407 161(±)--(3-Hydroxymethyl)piperazin-1-yl H H 4-Fluoro-phenyl H 215-219 405162 4-(2-Hydroxyethyl)piperazin-1-yl H H 3-Fluoro-5-methyl-phenyl H187-189 433 163 4-(2-hydroxyethyl)piperazin-1-yl H H 4-Fluoro-phenylMe-amino 207-209 448 164 4-(2-Hydroxy-2-methyl-propyl)piperazin-1-yl H H4-Fluoro-phenyl H 212-214 447 1654-(2-Hydroxy-2-methyl-propyl)piperazin-1-yl H Me 4-Fluoro-phenyl H205-207 461 166 4-(2-Hydroxy-2-methyl-propyl)piperazin-1-yl Me H4-Fluoro-phenyl H 219-221 461 1674-(2-hydroxy-2-methyl-propyl)piperazin-1-yl H H 4-Fluoro-phenyl Me-amino182-184 476 168 3-(1-hydroxy-1-methyl-ethyl)-piperazin-1-yl H H4-Fluoro-phenyl H 184-186 433 169 (R)-3-Isopropylpiperazin-1-yl H H4-Fluorophenyl H 179-181 417 170 (R)-3-Isopropyl-piperazin-1-yl H H4-Fluoro-phenyl Me-amino 172-174 446 171 4-Isopropyl-piperazin-1-yl H H3-Fluoro-phenyl MeO 124-126 447 172 4-Isopropyl-piperazin-1-yl Me H4-Fluoro-phenyl H 210-212 431 173 4-Isopropyl-piperazin-1-yl H Me4-Fluoro-phenyl H 195-197 431 174 4-Isopropyl-piperazin-1-yl H H4-Fluoro-phenyl Me-amino 207-209 446 175 4-Isopropylpiperazin-1-yl H H3,4-Difluorophenyl MeO 136-138 465 176 4-Isopropyl-piperazin-1-yl H H3-Fluoro-5-methyl-phenyl H 161-163 431 177(±)-3,6-diaza-bicyclo[3.2.0]hept-2-yl H H Phenyl H 212-128 369 178(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl H H Phenyl H N.D. 369 179(1S,4S)-6-2,5-Diaza-bicyclo[2.2.1]hept-2-yl H H 4-Fluoro-phenyl Me-amino191-193 416 180 (1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl H H4-Fluoro-phenyl H 178-180 401 181-189 181(1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl Me H 4-Fluoro-phenylH 185-187 415 182 (1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl HMe 4-Fluoro-phenyl H 212-214 415 183(1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl H H 4-Fluoro-phenylMe 156-158 415 184 1-(1S,4S)-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-methyl-propan-2-ol  

H H Phenyl H ND CF₃COOH (3:1) 441 185 3,6-Diaza-bicyclo[3.1.1]hept-3-ylH H 4-Fluoro-phenyl H 244-246 387 186 5-methyl-hexahydro-pyrrolo[3,4-c]H H 4-Fluoro-phenyl H 166-169 415 pyrrol-2(1H)-yle 1875-methyl-hexahydro-pyrrolo[3,4-c] Me H 4-Fluoro-phenyl H 164-166 429pyrrol-2(1H)-yle 188 5-methyl-hexahydro-pyrrolo[3,4-c] H Me4-Fluoro-phenyl H 235-238 429 pyrrol-2(1H)-yle 1895-methyl-hexahydro-pyrrolo[3,4-c] H Me 4-Fluoro-phenyl Me 219-221 443pyrrol-2(1H)-yle 190 5-methyl-hexahydro-pyrrolo[3,4-c] H H4-Fluoro-phenyl Me-amino 211-213 444 pyrrol-2(1H)-yle 1915-methyl-hexahydro-pyrrolo[3,4-c] H H 4-Fluoro-phenyl MeO 205-207 445pyrrol-2(1H)-yle 192 5-methyl-hexahydro-pyrrolo[3,4-c] H H4-Fluoro-phenyl Me 173-178 429 pyrrol-2(1H)-yle 1935-methyl-hexahydro-pyrrolo[3,4-c] H Me 4-Fluoro-phenyl Me-amino 190-192458 pyrrol-2(1H)-yle 194 5-methyl-hexahydro-pyrrolo[3,4-c] Me H4-Fluoro-phenyl Me-amino 211-213 458 pyrrol-2(1H)-yle 195(±)-Hexahydro-pyrrolo[3,4-b]-ylpyrrol-5(1H)-yl H H 4-Fluoro-phenyl H237-239 401 196 (±)-Hexahydro-pyrrolo[3,4-b]pyrrol-5(1H)-yl H H4-Fluoro-phenyl H 244-246 401 197(−)-Hexahydro-pyrrolo[3,4-b]pyrrol-5(1H)-yl H H 4-Fluoro-phenyl H246-248 401 198 (±)-Hexahydro-pyrrolo[3,4-b]pyrrol-5(1H)-yl H H4-Fluoro-phenyl Me-amino 189-191 430 199(4aS,7aS)-Octahydro-pyrrolo[3,4-b]pyridin-6-yl H H Phenyl H 237-239 397200 (4aS,7aS)-Octahydro-pyrrolo[3,4-b]pyridin-6-yl H H Phenyl Me 203-206411 201 (4aR,7aR)-Octahydro-pyrrolo[3,4-b]pyridin-6-yl H H Phenyl Me199-201 411 202 (4aS,7aS)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H Me4-Fluoro-phenyl H 217-219 429 203(4aS,7aS)-octahydro-pyrrolo[3,4-b]pyridin-6-yl Me H 4-Fluoro-phenyl H234-236 429 204 (4aR,7aR)-octahydro-pyrrolo[3,4-b]pyridin-6-yl Me H4-Fluoro-phenyl H 229-231 429 205(4aS,7aS)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H H 4-Fluoro-phenyl H238-240 415 206 (4aS,7aS)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H H4-Fluoro-phenyl Me 219-221 429 207 Octahydro-pyrrolo[3,4-b]pyridin-6-ylH H 4-Fluoro-phenyl Me-amino 244-246 444 208(4aR,7aR)-Octahydro-pyrrolo[3,4-b]pyridin-6-yl H H Phenyl H 234-236 297209 (4aR,7aR)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H H 4-Fluoro-phenyl H222-224 415 210 (4aR,7aR)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H H4-Fluoro-phenyl Me 220-222 429 211(4aR,7aR)-octahydro-pyrrolo[3,4-b]pyridin-6-yl H Me 4-Fluoro-phenyl H219-221 429 212 (±)-2,7-Diaza-spiro[4.4]non-2-yl H Me 4-Fluoro-phenyl H219-222 429 213 6,9-Diaza-spiro[4.5]dec-9-yl H H 4-Fluoro-phenyl H209-211 429 214 (±)-2,8-Diaza-spiro[5.5]dec-2-yl H Me 4-Fluoro-phenyl H215-218 457 215 2,9-Diaza-spiro[5.5]undec-9-yl H Me 4-Fluoro-phenyl H242-245 457 216 2,9-Diaza-spiro[5.5]undec-9-yl H H 4-Fluoro-phenylMe-amino 238-241 472 217 2,9-Diaza-spiro[5.5]undec-9-yl H H3,4-Difluorophenyl H 227-229 461 218 2,9-Diaza-spiro[5.5]undec-9-yl H H3-Fluoro-5-methyl-phenyl H 172-175 457 2194-Pyrrolidin-1-yl-piperidin-1-yl H H 3-Fluoro-phenyl H N.D. 443 2204-pyrrolidin-1-yl-piperidin-1-yl H H 4-Fluoro-phenyl Me-amino 217-219472 221 4-((R)-3-fluoro-pyrrolidin-1-yl)-piperidin-1-yl H H4-Fluorophenyl H 208-210 461 2224-((R)-3-Hydroxy-pyrrolidin-1-yl)-piperidin-1-yl H H Phenyl H 154-158441 223 4-((R)-3-Hydroxy-pyrrolidin-1-yl)-piperidin-1-yl H H3-Fluoro-5-methyl-phenyl H 178-183 473

A subject the invention is also a process for preparing the compounds ofthe invention of formula (I).

In accordance with the invention, the compounds of general formula (I)may be prepared according to the general process described in Scheme 1below.

In the text hereinbelow, the term “leaving group” means a group that canbe readily cleaved from a molecule by breaking a heterolytic bond, withloss of an electron pair. This group may thus be readily replaced withanother group during a substitution reaction, for example. Such leavinggroups are, for example, halogens or an activated hydroxyl group such asa mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups andreferences for preparing them are given in “Advances in OrganicChemistry”, J. March, 3^(rd) Edition, Wiley Interscience, pp. 310-316.

Scheme 1, Route 1: Introduction of the Amine

In general, and as illustrated in Scheme 1, the6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, R₃, A, L, B, R₇ and R₈ are as defined above maybe prepared from a 3-pyrid-4-ylimidazo[1,2-b]pyridazine derivative ofgeneral formula (IIa), in which R₂, R₃, R₇ and R₈ are as defined aboveand X₆ represents a leaving group such as a halogen, by treatment withan amine of general formula (IIIa) in which A, L and B are as definedabove. This reaction may be performed by heating the reagents in a polarsolvent such as dimethyl sulfoxide or aliphatic alcohols, for examplepentanol.

Scheme 1, Route 2: Construction of the Heterocycle

The 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, R₃, A, L, B, R₇ and R₈ are as defined above mayalso be prepared by condensation between a pyridazin-3-ylaminederivative of general formula (Vb) in which A, L, B, R₇ and R₈ are asdefined above and a 2-bromo-2-(pyrid-4-yl)ethan-1-one derivative ofgeneral formula (VIb) in which R₂ and R₃ are as defined above.

The reaction may be performed by heating the reagents in a polar solventsuch as aliphatic alcohols, for example ethanol or butanol.

Scheme 1, Route 3: Introduction of Pyridine—Metal-Catalyzed C—HArylation

The 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, R₃, A, L, B, R₇ and R₈ are as defined above mayalso be prepared from a 6-aminoimidazo[1,2-b]pyridazine derivative ofgeneral formula (IId) in which R₂, A, L, B, R₇ and R₈ are as definedabove, by metal-catalyzed C—H arylation with a 4-iodopyridine of generalformula (IVd) in which R₃ is as defined above and X represents an iodineatom. This coupling may be performed in the presence of a catalyst suchas palladium acetate and of a mineral base such as potassium carbonate,and in a polar aprotic solvent such as dimethylformamide.

Scheme 1, route 4: Introduction of Pyridine—Coupling of “Stille” or“Suzuki” Type

The 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, R₃, A, L, B, R₇ and R₈ are as defined above mayalso be prepared from a 6-amino-3-iodo- or3-bromo-imidazo[1,2-b]pyridazine derivative of general formula (IIc), inwhich R₂, A, L, B, R₇ and R₈ are as defined above and X represents abromine or iodine atom, via coupling under Stille or Suzuki conditionswith a stannane or a pyridine boronate of general formula (IVc) in whichR₃ is as defined above and M represents a trialkylstannyl group, usuallya tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group,usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group.

The couplings according to the Stille method are performed, for example,by heating in the presence of a catalyst such astetrakis(triphenylphosphine)palladium or copper iodide in a solvent suchas N,N-dimethylacetamide.

The couplings according to the Suzuki method are performed, for example,by heating in the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and of a mineralbase such as cesium carbonate in a solvent mixture such astetrahydrofuran and water.

Particular Synthetic Strategies

1. Synthetic Strategy when R₃═H, alkyl

Specifically, according to Scheme 2, the6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, A, L, B, R₇ and R₈ are as defined above, and inwhich R₃ represents a hydrogen atom or a group C₁₋₃-alkyl, may beprepared in two steps from a 6-aminoimidazo[1,2-b]pyridazine derivativeof general formula (IId) as defined above. Thus, the reaction of a6-aminoimidazo[1,2-b]pyridazine derivative of general formula (IId) witha mixture of a pyridine derivative of general formula (IVe) in which R₃represents a hydrogen atom or a group C₁₋₃-alkyl, and of an alkylchloroformate, for example ethyl chloroformate, leads to the derivativeof general formula (IIe) in which R₂, A, L, B, R₇ and R₈ are as definedabove and in which R₃ represents a hydrogen atom or a group C₁₋₃-alkyl.The derivative of general formula (IIe) is then oxidized usingortho-chloranil in a solvent such as toluene to give the6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (I) in which R₂, A, L, B, R₇ and R₈ are as defined above and inwhich R₃ represents a hydrogen atom or a group C₁₋₃-alkyl.

2. Synthetic Strategies when R₃═NH₂, NH—C₁₋₃ alkyl, N(—C₁₋₃ alkyl)(C₁₋₃alkyl), hydroxyl, C₁₋₃ alkyloxy.

According to Scheme 3, the 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (I) in which R₂, A, L, B, R₇ and R₃ areas defined above and in which R₃ represents an amino,C₁₋₃-monoalkylamine, or di-C₁₋₃ alkylamine, hydroxyl or C₁₋₃ alkyloxygroup may be prepared from a6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivative of generalformula (IIf) in which R₂, A, L, B, R₇ and R₈ are as defined above andin which X₃ represents a halogen atom or a leaving group.

When R₃ represents an amino, C₁₋₃ monoalkylamine or di-C₁₋₃ alkylaminegroup, the reaction may be performed by nucleophilic substitution usingthe corresponding primary or secondary amine in an aprotic solvent suchas N-methylpyrrolidone.

When R₃ represents an amino group, the reaction may also be performed intwo steps by coupling with benzhydrylideneamine in the presence of acatalyst such as tris(dibenzylideneacetone)dipalladium(0), a base suchas sodium tert-butoxide and a phosphonic ligand such as(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, followed by hydrolysisof the benzhydrylidene using an acid such as hydrochloric acid.

When R₃ represents a hydroxyl group, the reaction may be performed byheating in the presence of sodium hydroxide or potassium hydroxide in asolvent such as tert-butanol.

When R₃ represents a group C₁₋₃ alkoxy, the reaction may be performed bytreatment using the corresponding sodium or potassium C₁₋₃ alkoxide in asolvent such as N-methylpyrrolidone.

Synthesis of the Precursors

According to Scheme 4, the 3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (IIa), in which R₂, R₃, R₇ and R₈ are asdefined above and X₆ represents a leaving group such as a halogen, maybe prepared by condensation between a pyridazin-3-ylamine derivative ofgeneral formula (Va) in which R₇ and R₈ are as defined above and X₆represents a halogen or a leaving group and a2-bromo-2-(pyrid-4-yl)ethan-1-one derivative of general formula (VIa) inwhich R₂ and R₃ are as defined above.

The reaction may be performed by heating the reagents in a polar solventsuch as aliphatic alcohols, for example ethanol or butanol.

According to Scheme 5a, the 3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (IIf), in which R₂, A, L, B, R₇ and R₈are as defined above and X₃ represents a leaving group such as ahalogen, may be prepared by condensation between a pyridazin-3-ylaminederivative of general formula (Vb) in which A, L, B, R₇ and R₈ are asdefined above and a 2-bromo-2-(pyrid-4-yl)ethan-1-one derivative ofgeneral formula (VIf) in which R₂ is as defined above and X₃ representsa halogen or a leaving group.

This reaction may be performed by heating the reagents in a polarsolvent such as aliphatic acids, for example ethanol or butanol.

According to Scheme 5b, the 3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (IIf) as defined above may also beobtained from a 6-amino-3-iodo- or 3-bromo-imidazo[1,2-b]pyridazinederivative of general formula (IIc), in which R₂, A, L, B, R₇ and R₈ areas defined above and X represents a bromine or iodine atom, by couplingunder the Stille or Suzuki conditions with a stannane or a pyridineboronate of general formula (IVe) in which X₃ represents a halogen or aleaving group and M represents a trialkylstannyl group, usually atributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group,usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group.

The couplings according to the Stille method are performed, for example,by heating in the presence of a catalyst such astetrakis(triphenylphosphine)palladium or copper iodide in a solvent suchas N,N-dimethylacetamide.

The couplings according to the Suzuki method are performed, for example,by heating in the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and of a mineralbase such as cesium carbonate in a mixture of solvents such astetrahydrofuran and water.

According to Scheme 6, the 3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (IIa), in which R₂, R₃, R₇ and R₈ are asdefined above and X₆ represents a leaving group such as a halogen mayalso be prepared in two steps from an imidazo[1,2-b]pyridazinederivative of general formula (VIIIa) in which R₂, R₇ and R₈ are asdefined above and X₆ represents a leaving group.

The bromination or iodination of an imidazo[1,2-b]pyridazine derivativeof general formula (VIIIa), in which R₂, R₇ and R₈ are as defined aboveand X₆ represents a halogen atom or a leaving group, leads to a 3-bromo-or iodoimidazo[1,2-b]pyridazine derivative of general formula (VIIa), inwhich R₂, R₇ and R₈ are as defined above and X₆ represents a halogen ora leaving group and X represents a bromine or iodine atom. This reactionmay be performed using N-bromo- or iodosuccinimide or iodinemonochloride in a polar solvent such as acetonitrile, tetrahydrofuran,methanol or chloroform.

The 3-bromo or iodoimidazo[1,2-b]pyridazine derivative of generalformula (VIIa) obtained is then regioselectively coupled according tothe Stille or Suzuki methods with a stannane or a pyridine boronate ofgeneral formula (IVc) in which R₃ is as defined above and M represents atrialkylstannyl group, usually a tributylstannyl group or a groupdihydroxyboryl or dialkyloxyboryl group, usually a4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group.

The couplings according to the Stille method are performed, for example,by heating in the presence of a catalyst such astetrakis(triphenylphosphine)palladium or copper iodide in a solvent suchas dimethylacetamide.

The couplings according to the Suzuki method are performed, for example,by heating in the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and of a mineralbase such as cesium carbonate in a mixture of solvents such astetrahydrofuran and water.

The imidazo[1,2-b]pyridazine derivatives of general formula (VIIIa) inwhich R₂, R₇ and R₈ are as defined above and X₆ represents a leavinggroup are known or may be prepared by analogy with methods described inthe literature (Abignente, Enrico; Caprariis, Paolo de; Patscot,Rosaria; Sacchi, Antonella; J. Heterocycl. Chem.; 23; 1986; 1031-1034;Barlin, Gordon B.; Davies, Les P.; Ireland, Stephen J.; Ngu, Maria M.L.; Zhang, Jiankuo; Aust. J. Chem.; EN; 45; 4; 1992; 731-749; Mourad,Alaa E.; Wise, Dean S.; Townsend, Leroy B.; J. Heterocycl. Chem.; 30; 5;1993; 1365-1372; Pollak et al.; Tetrahedron; 24; 1968; 2623; Hervet,Maud; Galtier, Christophe; Enguehard, Cecile; Gueiffier, Alain; Debouzy,Jean-Claude; Journal of Heterocyclic Chemistry (2002), 39(4), 737-742).

According to Scheme 7, the 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazinederivatives of general formula (IIc) in which R₂, A, L, B, R₇ and R₈ areas defined above and in which X represents a bromine or iodine atom areprepared by bromination or iodination of a6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine starting derivative ofgeneral formula (IId) in which R₂, A, L, B, R₇ and R₈ are as definedabove.

This reaction may be performed using N-bromo- or iodosuccinimide oriodine monochloride in a polar aprotic solvent such as acetonitrile ortetrahydrofuran.

The 6-amino-3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of generalformula (IId) in which R₂, A, L, B, R₇ and R₈ are as defined above areknown or may be prepared by analogy with methods described in theliterature (for example Watanabe et al.; Synthesis; 1977; 761; Jurgee etal.; J. Heterocycl. Chem.; 12; 1975; 253.255; Werbel, L. M.; Zamora, M.L.; J. Heterocycl. Chem.; 2; 1965; 287-290; Yoneda et al.; Chem. Pharm.Bull.; 12; 1964; 1351.1353.1354; Tomoyasu; Iizawa, Yuji; Okonogi, Kenji;Miyake, Akio; J. Antibiot.; 53; 10; 2000; 1053-1070).

They are usually prepared by condensation between a pyridazin-3-ylaminederivative of general formula (Vb) in which A, L, B, R₇ and R₈ are asdefined above and a 2-bromo, chloro- or iodoethan-1-one derivative ofgeneral formula (VId) in which R₂ is as defined above. The reaction maybe performed by heating the reagents in a polar solvent such as ethanolor butanol.

In the preceding synthetic schemes, the starting compounds and thereagents, when their mode of preparation is not described, arecommercially available or described in the literature, or alternativelymay be prepared according to methods that are described therein or thatare known to those skilled in the art.

Protecting Groups

For the compounds of general formula (I), (IIc), (IId), (IIe), (IIf),(IIIa) and (Vb) as defined above and when the group N-A-L-B comprises aprimary or secondary amine function, this function may optionally beprotected during the synthesis with protecting groups known to thoseskilled in the art, for example a benzyl or a t-butyloxycarbonyl.

For the compounds of general formula (I), (IIa), (IVc), (IVd), (VIa) and(VIb) as defined above and when the group R₃ comprises a primary orsecondary amine function, this function may be optionally protected withprotecting groups known to those skilled in the art, for example abenzyl or a t-butyloxycarbonyl.

The products of general structure (I) as defined above are obtainedaccording to the processes described after a final additional step ofdeprotection of the protecting group according to the usual conditionsknown to those skilled in the art.

The examples that follow describe the preparation of certain compoundsin accordance with the invention. These examples are not limiting andserve merely to illustrate the present invention. The numbers of theillustrated compounds refer to those given in the table below, whichillustrates the chemical structures and physical properties of a numberof compounds according to the invention.

EXAMPLE 1 (Compound 50):2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine

a) Synthesis According to the Process of Scheme 1, Route 4:

Step 1.1a.2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

After heating a suspension of 32 g (97.4 mmol) of6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS No.: 2069-47-8)in 200 ml of 1-methylpiperazine at 160° C. for 16 hours, the mixture ispoured into 1.5 L of water. The yellowish precipitate formed isseparated out by filtration and rinsed with cold isopropanol and thenwith diisopropyl ether. 30 g of a beige-colored powder are thus isolatedafter drying under vacuum.

m.p.: 190° C.

¹H NMR (CDCl₃) δ: 7.85 (s; 1H), 7.8 (m, 2H), 7.60 (d, 1H), 7.05 (pseudot, 2H), 6.75 (d, 1H), 3.45 (m, 4H), 2.50 (m, 4H), 2.30 (s, 3H) ppm.

Step 1.2a.2-(4-Fluorophenyl)-3-iodo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

To a solution, cooled to about 5° C., of 31.0 g (99.6 mmol) of2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine inchloroform is rapidly added dropwise a solution of 64.7 g (398 mmol) ofiodine monochloride in 150 mL of methanol. Mild exothermicity and theformation of a precipitate during the addition are observed. Aftercooling to room temperature and stirring for 30 minutes, the mixture ispoured into 2 L of aqueous 5% sodium thiosulfate solution saturated withsodium bicarbonate. After vigorous stirring until the mixture hasdecolorized, the product is extracted with chloroform. The organic phaseis separated out, dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a brown solid. This solid is trituratedin a mixture of 400 mL of diisopropyl ether and 50 mL of isopropanol atreflux. After cooling, 40 g of a beige-colored powder are isolated byfiltration through a sinter funnel and drying under vacuum.

m.p.: 180° C.

¹H NMR (CDCl₃) δ: 8.05 (pseudo dd; 2H), 7.65 (d, 1H), 7.15 (pseudo t,2H), 6.85 (d, 1H), 3.65 (m, 4H), 2.55 (m, 4H), 2.35 (s, 3H) ppm.

Step 1.3a.2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine

To a suspension of 2.80 g (6.40 mmol) of2-(4-fluorophenyl)-3-iodo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazinein 200 mL of a mixture of dimethoxyethane and water (9:1), are added1.36 g (12.8 mmol) of sodium bicarbonate and 0.95 g (7.7 mmol) of(pyrid-4-yl)boronic acid. After sparging with a stream of argon for afew moments, 0.21 g (0.26 mmol) of a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane (PdCl₂(dppf).CH₂Cl₂) is added and the reaction mixtureis refluxed under argon for 18 hours. A further 0.95 g (7.7 mmol) of(pyrid-4-yl)boronic acid, 0.21 g (0.26 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane and 10 mL of water are then added. Heating is continuedfor 24 hours. The solvent is then evaporated off under reduced pressureand the brown residue is triturated with aqueous 3N hydrochloric acidand then filtered on a Büchner funnel. The aqueous phase is washed twicewith diethyl ether and then cautiously neutralized, using aqueousammonia diluted with ice, to basic pH. The product is extracted withchloroform, the organic phase is dried over sodium sulfate and filtered,and the solvent is evaporated off to give 2.5 g of a yellowish powder.

The product is purified by chromatography on silica gel, eluting with amixture of dichloromethane, methanol and aqueous ammonia (96/4/0.4) togive 2.3 g of a whitish powder. The product is recrystallized from amixture of 130 mL of acetonitrile and 10 to 30 mL of isopropanol.

1.1 g of a whitish powder are isolated.

m.p.: 248-250° C.

¹H NMR (CDCl₃) δ: 8.65 (d; 2H), 7.85 (d, 1H), 7.5-7.7 (m, 4H), 7.05(pseudo t, 2H), 6.95 (d, 1H), 3.55 (m, 4H), 2.55 (m, 4H), 2.40 (s, 3H)ppm.

b) Synthesis According to the Process of Scheme 2:

Step 1.1b. Ethyl4-[2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-4H-pyridine-1-carboxylate

To a suspension, cooled to about 0° C., of 3.24 g (10.4 mmol) of2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in7.5 mL of pyridine is added dropwise a solution of 5.0 mL (52 mmol) ofethyl chloroformate. After cooling to room temperature, 10 mL (104 mmol)of ethyl chloroformate and 15 mL of pyridine are added in two portions.

After 18 hours, the mixture is diluted with 50 mL of dichloromethane and20 mL (208 mmol) of ethyl chloroformate are added in three portions over5 hours. 350 mL of water are then added, and the organic phase isseparated out and washed twice with water, dried over sodium sulfate andconcentrated under reduced pressure to give 4.5 g of a brownish solid.This solid is triturated in diethyl ether to give 3.5 g of beige-coloredcrystals. The solid is dissolved in dichloromethane and purified bychromatography on a column of silica gel, eluting with a mixture of 10%methanol in dichloromethane, to give 2.95 g of pale yellow crystalsafter trituration in diethyl ether, filtering through a sinter funneland drying under vacuum.

m.p.: 179.9° C.

¹H NMR (DMSO-d₆) δ: 7.80 (d; 2H), 7.65 (m, 2H), 7.2 (m, 3H), 6.95 (d,1H), 4.8-5.0 (m, 3H), 4.25 (q, 2H), 3.40 (m, 4H), 2.40 (m, 4H), 2.20 (s,3H), 1.30 (t, 3H) ppm.

Step 1.2b.2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine

To a suspension of 1.00 g (2.16 mmol) of ethyl4-[2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-4H-pyridine-1-carboxylatein 35 mL of toluene is added a solution of 0.65 g (2.6 mmol) ofortho-chloranil in 6 mL of toluene. After reaction for 6 hours, 60 mL of1N sodium hydroxide are added and the product is extracted with ethylacetate. The organic phase is washed with saturated aqueous sodiumchloride solution and dried over sodium sulfate, and the solvent isevaporated off under reduced pressure. 1.2 g of solid are thusrecovered, and are purified on a column of silica gel, eluting with astepwise gradient of 3% to 15% methanol in dichloromethane. The productobtained is washed with diisopropyl ether and recrystallized fromisopropyl alcohol to give 0.47 g of crystals after filtering off anddrying under reduced pressure.

m.p.: 294-296° C.

¹H NMR (CDCl₃) δ: 8.65 (d; 2H), 7.85 (d, 1H), 7.5-7.7 (m, 4H), 7.05(pseudo t, 2H), 6.95 (d, 1H), 3.55 (m, 4H), 2.55 (m, 4H), 2.40 (s, 3H)ppm.

c) Synthesis According to Scheme 1, Route 3:

Step 1.1c.2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine

A mixture of 0.90 g (2.89 mmol) of2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine(Synthesis, 2001, 4, 595-600), 0.71 g (3.5 mmol) of 4-iodopyridine,0.032 g (0.14 mmol) of palladium acetate and 0.48 g (3.5 mmol) ofpotassium carbonate in 18 mL of dimethylformamide is heated at 135° C.for 18 hours. After cooling, the reaction medium is poured into waterand the product is extracted with ethyl acetate. The organic phase iswashed with water and dried over sodium sulfate, and the solvent isevaporated off under reduced pressure. The residue is purified on acolumn of silica gel, eluting with a mixture of dichloromethane,methanol and aqueous ammonia (95/5/0.5) to give 0.5 g of crystals afterrecrystallization from acetonitrile, filtering off and drying underreduced pressure.

m.p.: 250° C.

¹H NMR (CDCl₃) δ: 8.65 (d, 2H), 7.85 (d, 1H), 7.5-7.7 (m, 4H), 7.05(pseudo t, 2H), 6.95 (d, 1H), 3.55 (m, 4H), 2.55 (m, 4H), 2.40 (s, 3H)ppm.

EXAMPLE 2 (Compound 3):2-(4-Fluorophenyl)-7,8-dimethyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine

Synthesis According to Scheme 1, Route 4:

Step 2.1.6-Chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine

A solution of 13 g (85 mmol) of 3-amino-6-chloro-4,5-dimethylpyridazineand 23 g (107 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone in 130 mL ofethanol is refluxed for 16 hours. After cooling, the solvent isevaporated off under reduced pressure and the residue is taken up inchloroform. The organic phase is washed with diluted aqueous ammonia,dried over sodium sulfate and concentrated under reduced pressure togive a brown solid. This solid is triturated in acetone to give 19.2 gof a beige-colored powder.

Yield: 84%

m.p.: 172-174° C.

¹H NMR (CDCl₃) δ: 8.10 (s, 1H), 7.95 (m, 2H), 7.15 (pseudo t, 2H), 2.70(s, 3H), 2.45 (s, 3H) ppm.

Step 2.2.2-(4-Fluorophenyl)-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine

A mixture of 1.4 g (5.08 mmol) of6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 8.7g (100 mmol) of piperazine is heated at 150° C. for 3 hours in areactor. The medium is then poured into water and the precipitate formedis isolated by filtration. The product is then recrystallized from amixture of diisopropyl ether and isopropanol to give 1.15 g of a whitepowder.

Yield: 70%.

¹H NMR (CDCl₃) δ: 8.00 (s; 1H), 7.95 (pseudo dd, 2H), 7.15 (pseudo t,2H), 3.15 (m, 8H), 2.65 (s, 3H), 2.35 (s, 3H) ppm.

Step 2.3.2-(4-Fluorophenyl)-3-iodo-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine

To a solution, cooled to 0° C., of 1.15 g (3.53 mmol) of2-(4-fluorophenyl)-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazinein 20 mL of dichloromethane, is added dropwise a solution of 2.29 g(14.1 mmol) of iodine monochloride in 5 mL of methanol and the medium isstirred for 30 minutes at room temperature. 5% sodium thiosulfatesolution is then added and the medium is basified by addition of sodiumhydrogen carbonate.

The product is extracted with dichloromethane, the organic phase isdried over sodium sulfate and filtered, and the solvent is evaporatedoff to give 0.82 g of a yellow powder after crystallization from diethylether and drying.

Yield: 51%.

¹H NMR (CDCl₃) δ: 8.15 (pseudo dd, 2H), 7.35 (pseudo t, 2H), 3.15 (m,4H), 2.95 (m, 4H), 2.5 (s, 3H), 2.30 (s, 3H) ppm.

Step 2.4. tert-Butyl4-[2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate

A solution of 0.70 g (1.55 mmol) of2-(4-fluorophenyl)-3-iodo-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazineand 19 mg (0.16 mmol) of dimethylaminopyridine in 10 mL oftetrahydrofuran is treated with 0.41 g (1.9 mmol) of di-tert-butylcarbonate for 1 hour. The solvent is then evaporated off and the solidobtained is recrystallized from acetonitrile. 0.67 g of product is thusisolated after drying.

Yield: 78%.

¹H NMR (CDCl₃) δ: 8.00 (pseudo dd, 2H), 7.10 (pseudo t, 2H), 3.60 (m,4H), 3.15 (m, 4H), 2.55 (s, 3H), 2.25 (s, 3H), 1.40 (s, 9H) ppm.

Step 2.5. tert-Butyl4-[2-(4-fluorophenyl)-7,8-dimethyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate

To a mixture of 0.66 g (1.2 mmol) of tert-butyl4-[2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylatein 15 mL of a mixture of tetrahydrofuran and water (9:1), are added 1.17g (3.6 mmol) of cesium carbonate and 0.31 g (1.4 mmol) of(pyrid-4-yl)boronic acid. After sparging with a stream of argon for afew moments, 88 mg (0.11 mmol) of a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane (PdCl₂(dppf).CH₂Cl₂) are added and the reaction mixtureis refluxed under argon for 18 hours. The mixture is then poured intowater and the product is extracted with dichloromethane, the organicphase is dried over sodium sulfate and filtered, and the solvent isevaporated off to give a brown solid. The product is purified bychromatography on silica gel, eluting with a mixture of ethyl acetateand cyclohexane (3/7) to give 0.44 g of a white powder.

Yield: 73%

m.p.: 231-233° C.

¹H NMR (CDCl₃) δ: 8.55 (pseudo d, 2H), 7.55-7.75 (m, 4H), 7.00 (pseudot, 2H), 3.55 (m, 4H), 3.05 (m, 4H), 2.60 (s, 3H), 2.25 (s, 3H), 1.40 (s,9H) ppm.

Step 2.6.2-(4-Fluorophenyl)-7,8-dimethyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine

To a solution of 0.43 g (0.86 mmol) of tert-butyl4-[2-(4-fluorophenyl)-7,8-dimethyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylatein 5 mL of dichloromethane at 0° C. is added dropwise 0.64 mL (8.6 mmol)of trifluoroacetic acid. After stirring for 4 hours at room temperature,a further 0.64 mL (8.6 mmol) of trifluoroacetic acid is added and thereaction mixture is left for 18 hours. The solvent is then removed underreduced pressure and the residue is taken up in water. The resultingaqueous phase is washed with ether and then basified by addition ofaqueous sodium hydrogen carbonate solution. The product is extractedwith dichloromethane, the organic phase is dried over sodium sulfate andfiltered, and the solvent is evaporated off to give 0.285 g of a whitepowder.

Yield: 83%

m.p.: 233-235° C.

¹H NMR (CDCl₃) δ: 8.60 (pseudo d, 2H), 7.55-7.75 (m, 4H), 7.05 (pseudot, 2H), 3.00-3.2 (m, 4H), 2.65 (s, 3H), 2.35 (s, 3H) ppm.

EXAMPLE 3 (Compound 58):{4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}dimethylamine

Synthesis According to Scheme 3:

Step 3.1. 6-(4-Benzylpiperazin-1-yl)pyridazin-3-ylamine

48.9 g (278 mmol) of 1-benzylpiperazine and 12.0 g (92.6 mmol) of3-amino-6-chloropyridazine are heated at 160° C. for 1 hour. The brownoil obtained is poured into 500 mL of aqueous sodium bicarbonatesolution and the product is extracted with dichloromethane. The organicphase is dried and then concentrated under reduced pressure. The oilobtained is triturated in diethyl ether, and 20.5 g of a solid areisolated after filtering off and drying.

Yield: 82%.

¹H NMR (CDCl₃) δ: 7.45-7.65 (m, 6H), 7.20 (s, 1H), 5.5 (broad unresolvedcomplex, 2H) 3.80 (s, 2H), 3.60-3.75 (m, 4H), 2.80-2.85 (m, 4H) ppm.

Step 3.2.2-(4-Fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

Synthesis According to Scheme 5a:

A mixture of 0.77 g (2.5 mmol) of2-bromo-1-(4-fluorophenyl)-2-(2-fluoropyrid-4-yl)ethanone (CAS No.:302839-10-7) and 0.57 g (3.0 mmol) of6-(4-methylpiperazin-1-yl)pyridazin-3-ylamine (CAS No.: 66346-94-9) in15 mL of ethanol is refluxed for 1 hour 30 minutes. After cooling, themedium is taken up in chloroform and washed with saturated aqueoussodium bicarbonate solution.

The organic phase is then dried over sodium sulfate and concentratedunder reduced pressure to give an orange-colored solid.

The solid obtained is purified by chromatography on silica gel (7 g),eluting with a mixture of dichloromethane, methanol and aqueous ammonia(95/5/0.5). The product obtained is crystallized from refluxingacetonitrile to give 0.76 g of a white powder after filtering off anddrying.

m.p.: 250-255° C.

¹H NMR (CDCl₃) δ: 8.20 (d, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.4 (m, 2H),7.10 (m, 2H), 6.95 (d, 1H), 3.60 (m, 4H), 2.60 (m, 4H), 2.40 (s, 3H)ppm.

Step 3.3.{4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}dimethylamine

0.10 g (0.25 mmol) of2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazineand 10 mL of dimethylamine are introduced into an autoclave. The mixtureis heated at 150° C. overnight and then cooled and poured into water.The product is extracted with chloroform, and the organic phase is driedover sodium sulfate and then concentrated under reduced pressure to givea solid. This solid is crystallized and recrystallized from acetonitrileto give 0.028 g of a white powder after cooling, filtering off anddrying.

m.p.: 180-183° C.

¹H NMR (CDCl₃) δ: 8.15 (d, 1H), 7.70 (d, 1H), 7.70 (m, 2H), 6.95 (m,2H), 6.80 (m, 2H), 6.70 (d, 1H), 3.50 (m, 4H), 3.00 (s, 6H), 2.50 (m,4H), 2.30 (s, 3H) ppm.

EXAMPLE 4 (Compound 59):2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

Synthesis According to Scheme 3:

To a solution under argon of 0.10 g (0.25 mmol) of2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazinein N-methylpyrrolidone is added 0.65 mL (3.4 mmol) of sodium methoxideat 30% by weight in methanol. After stirring for 4 days at roomtemperature, the medium is poured into 200 mL of water and the productis extracted with ethyl acetate. The organic phase is dried over sodiumsulfate and then concentrated under reduced pressure to give a paleyellow solid.

The solid obtained is purified by chromatography on silica gel (7 g),eluting with a mixture of dichloromethane, methanol and aqueous ammonia(95/05/0.5). The product obtained is crystallized from refluxingacetonitrile to give 0.04 g of a white powder after cooling, filteringoff and drying.

m.p.: 189-194° C.

¹H NMR (CDCl₃) δ: 8.20 (d, 1H), 7.80 (d, 1H), 8.6 (m, 2H), 7.15-6.95 (m,4H), 6.90 (d, 1H), 4.00 (s, 3H), 3.55 (m, 4H), 2.55 (m, 4H), 2.40 (s,3H) ppm.

EXAMPLE 5 (Compound 4):4-[2-(4-Fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

Step 5.1. 2-(4-Fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine

Into a reactor containing 94 g (823 mmol) of 98% 1-formylpiperazine at135° C. are added 26.5 g (107 mmol) of2-(4-fluorophenyl)-6-chloro-imidazo[1,2-b]pyridazine and the reactor isthen closed and maintained at 135° C. for 2 hours 30 minutes.

The reactor is then cooled and the reaction medium is poured into 1.5 Lof water. The yellowish solid is isolated by filtration and taken up in700 mL of tetrahydrofuran. 800 mL of 4N sulfuric acid are then added andthe solution is refluxed overnight.

The mixture is filtered while hot and the filtrate is partiallyconcentrated under reduced pressure. This aqueous phase is washed twicewith diethyl ether and then basified using cold aqueous ammoniasolution. The precipitate formed is stirred for 30 minutes and isolatedby filtration through a sinter funnel and washing with water. The solidis taken up in chloroform and the organic phase obtained is washed withwater, dried over sodium sulfate and then concentrated under reducedpressure to give a brown-yellow solid. 21.5 g of a pale of yellow powderare isolated by clarification in a mixture of 200 mL of diisopropylether and 10 mL of isopropanol at reflux, followed by cold filtrationand drying.

m.p.: 200-203° C.

Yield: 61%.

¹H NMR (CDCl₃) δ: 8.05 (s, 1H), 7.85 (m, 2H), 7.65 (d, 1H), 7.05 (m,2H), 6.94 (d, 1H), 3.40 (s, 4H), 2.85 (s, 4H) ppm.

Step 5.2. tert-Butyl4-[2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate

To a solution of 21.5 g (72.3 mmol) of2-(4-fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine and 0.44 g(3.6 mmol) of dimethylaminopyridine in 500 mL of chloroform is addeddropwise a solution of tert-butyl anhydride dissolved in 100 mL ofchloroform. After stirring for 30 minutes at room temperature, themedium is poured into saturated aqueous sodium hydrogen carbonatesolution. The organic phase obtained is washed with water, dried oversodium sulfate and then concentrated under reduced pressure to give abrown solid. Finally, 28.0 g of a beige-colored powder are isolatedafter trituration in a mixture of 200 mL of diisopropyl ether and 10 mLof isopropanol at reflux, followed by cold filtration and drying.

Yield: 97%.

¹H NMR (CDCl₃) δ: 7.78-8.00 (m, 3H), 7.80 (d, 1H), 7.15 (pseudo t, 1H).6.85 (d, 1H), 3.45-3.7 (m, 8H), 1.5 (s, 9H) ppm.

Step 5.3. tert-Butyl4-[2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate

To a solution of 28.0 g (70.5 mmol) of tert-butyl4-[2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylatein 800 mL of tetrahydrofuran cooled to about 0° C. are added 17.4 g(77.5 mmol) of N-iodosuccinimide. After stirring for 18 hours at roomtemperature, the solvent is evaporated off under reduced pressure.

The orange-red solid obtained is triturated in 1.5 L of water andseparated out by filtration. The solid is then taken up in chloroformand the organic phase obtained is washed with 1 L of 5% sodiumthiosulfate solution, dried over sodium sulfate and then concentratedunder reduced pressure to give a brown solid.

32.8 g of a pale of yellow powder are finally isolated by clarificationin a mixture of 300 mL of diisopropyl ether and 50 mL of isopropanol atreflux, followed by cold filtration and drying.

Yield: 89%

¹H NMR (CDCl₃) δ: 7.85 (pseudo q, 2H), 7.60 (d, 1H), 7.05 (pseudo t,1H). 6.75 (d, 1H), 3.5 (m, 8H), 1.4 (s, 9H) ppm.

Step 5.4. tert-Butyl4-[3-(2-chloropyrid-4-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate(according to Scheme 5b)

To a suspension of 1.25 g (2.39 mmol) of tert-butyl4-[2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylatein a mixture of tetrahydrofuran and water are added 2.33 g (7.17 mmol)of cesium carbonate and 0.45 g (2.9 mmol) of 2-chloropyridine-4-boronicacid. After sparging with a stream of argon for a few moments, 0.18 g(0.21 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloro)palladium(II)(PdCl₂(dppf)) is added and the reaction mixture is refluxed under argonfor 18 hours. The solvent is then stripped off under reduced pressure,the residue is taken up in chloroform, the organic phase obtained iswashed with water, dried over sodium sulfate and filtered, and thefiltrate is concentrated under reduced pressure. The brown solidobtained is purified by chromatography on silica gel (50 g), elutingwith a mixture of dichloromethane, methanol and aqueous ammonia(95/5/0.5). The product obtained is crystallized from 20 ml of refluxingacetonitrile to give 0.95 g of a white powder after cooling, filteringoff and drying.

Yield: 78%

¹H NMR (CDCl₃) δ: 8.25 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.45 (pseudoq, 2H), 7.25 (d, 1H), 6.95 (pseudo t, 2H), 6.80 (d, 1H), 3.25-3.50 (m,8H), 1.35 (s, 9H) ppm.

Step 5.5. tert-Butyl4-[3-[2-(benzhydrylideneamino)pyrid-4-yl]-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate

Synthesis According to Scheme 3:

To a suspension of 0.95 g (1.9 mmol) of tert-butyl4-[3-(2-chloropyrid-4-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylateand 0.41 g (2.2 mmol) of benzhydrylideneamine in 100 mL of anhydroustoluene are added under argon 0.25 g (2.6 mmol) of sodium tert-butoxideand 46 mg (0.075 mmol) of(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.

After sparging with a stream of argon for a few moments, 34 mg (0.037mmol) of tris(dibenzylideneacetone)dipalladium(0) are added and thereaction mixture is refluxed under argon for 18 hours. The medium isfiltered while hot and the solvent is then stripped off under reducedpressure. The residue is taken up in chloroform, the organic phaseobtained is washed with water, dried over sodium sulfate and filtered,and the filtrate is concentrated under reduced pressure. The brown solidobtained is purified by chromatography on silica gel (50 g), elutingwith a mixture of dichloromethane, methanol and aqueous ammonia(95/2/0.2). The product obtained is crystallized from a mixture of 20 mLof acetonitrile and 5 mL of n-butanol at reflux to give 0.80 g of awhite powder after cooling, filtering off and drying.

Yield: 65%

¹H NMR (CDCl₃) δ: 8.25 (d, 1H), 7.70 (m, 3H), 7.05-7.45 (m), 6.85-6.95(m, 4H), 6.80 (d, 1H), 3.55-3.30 (m, 8H), 1.40 (s, 9H) ppm.

Step 5.6.4-[2-(4-Fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

A suspension of 0.80 (1.22 mmol) of tert-butyl4-[3-[2-(benzhydrylideneamino)pyrid-4-yl]-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylatein 70 mL of aqueous hydrochloric acid is maintained at 80° C. for about1 hour 30 minutes. After cooling, the aqueous phase is washed twice withdiethyl ether and then basified by addition of ice-cold aqueous ammonia.The product is extracted with chloroform and the organic phase obtainedis washed with water, dried over sodium sulfate and filtered, and thefiltrate is concentrated under reduced pressure. The brown solidobtained is purified by chromatography on silica gel (35 g), elutingwith a mixture of dichloromethane, methanol and aqueous ammonia(90/10/1). The product obtained is crystallized from 20 mL of refluxingacetonitrile to give 0.38 g of a white powder after cooling, filteringoff and drying

m.p.: 255° C. (decomposition)

¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.80 (d, 1H), 7.60-7.70 (m, 2H),6.85-7.15 (m, 4H), 6.80 (s, 1H), 4.45 (broad unresolved complex, 2H),3.40-3.60 (m, 4H), 2.95-3.10 (m, 4H) ppm.

EXAMPLE 6 (Compound 113):4-[2-(4-Fluorophenyl)-6-[5-benzyl(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)]-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

Synthesis According to Scheme 1, Route 4:

Step 6.1.tert-Butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate

To a solution of 6.76 (24.8 mmol) of tert-butyl(4-bromopyrid-2-yl)carbamate (Deady, Leslie W.; Korytsky, Olga L.; Rowe,Jeffrey E.; Aust. J. Chem.; 35; 10; 1982; 2025-2034) in 150 mL ofdimethylformamide are added 8.0 g (81 mmol) of potassium acetatepredried at 130° C. and 6.9 g (27 mmol) of bis(pinacolato)diboron. Astream of argon is then sparged through for a few moments, and 1.2 g(1.5 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added.The mixture is stirred at 80° C. under argon for 2 hours and then pouredinto saturated aqueous ammonium chloride solution. The product isextracted with ethyl acetate, the organic phase is dried over sodiumsulfate and the solvent is stripped off under reduced pressure. Theresidue is triturated in 300 mL of refluxing diisopropyl ether and theinsoluble matter is separated out by filtration.

The filtrate is cooled and partially concentrated under reducedpressure. After adding 70 mL of hexane, the precipitate formed isisolated by filtration to give 4.2 g of an orange-colored solid afterdrying.

Yield: 53%

m.p.: 188-193° C.

¹H NMR (CDCl₃) δ: 8.15 (m, 2H), 7.65 (broad s, 1H), 7.15 (d, 1H), 1.40(s, 9H), 1.20 (s, 12H) ppm.

Step 6.2.6-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine

A mixture of 3.00 g (10.9 mmol) of6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 6.6g (33 mmol) of 2-benzyloctahydropyrrolo[3,4-c]pyrrole in 20 mL ofpentanol is heated at 150° C. for 2 days in a reactor. The medium isthen poured into aqueous 1N hydrochloric acid solution. The aqueousphase is washed with ethyl acetate and then basified with sodiumhydroxide.

The product is extracted with dichloromethane and the organic phase isdried over sodium sulfate and then concentrated under reduced pressure.The yellow oil obtained is chromatographed on silica gel, eluting withdichloromethane containing 3% methanol and 0.3% aqueous ammonia. Theproduct is then crystallized from diisopropyl ether to give 3.2 g of aslightly yellow powder.

m.p.: 115-117° C.

¹H NMR (CDCl₃) δ: 7.85 (m; 3H), 7.30 (m, 5H), 7.05 (pseudo t, 2H), 3.60(s, 2H), 3.30 (m, 2H), 3.10 (m, 2H), 2.80 (m, 4H), 2.55 (s, 3H), 2.35(m, 2H), 2.25 (s, 3H) ppm.

Step 6.3.6-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazine

To a solution, cooled to 0° C., of 3.2 g (7.3 mmol) of6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazinein 20 mL of chloroform is added dropwise a solution of 1.8 g (11 mmol)of iodine monochloride in 3 mL of methanol and the medium is stirred forone hour at room temperature. The medium is then basified by addition ofaqueous sodium hydrogen carbonate solution and 5% sodium thiosulfatesolution is then added until the medium has decolorized.

The product is extracted with chloroform, the organic phase is driedover sodium sulfate and filtered, and the solvent is evaporated off togive 3.2 g of a yellow powder after crystallization from diethyl etherand drying.

¹H NMR (DMSO-d₆) δ: 8.35 (m; 2H), 7.65 (m, 7H), 3.80 (s, 2H), 3.65 (m,2H), 3.40 (m, 2H), 3.07 (m, 2H), 2.90 (m, 2H), 2.65 (m, 2H), 2.5 (s, 3H)ppm.

Step 6.4. tert-Butyl{4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl}pyrid-2-yl]carbamate

To a solution of 3.60 g (6.34 mmol) of6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazinein 15 mL of a mixture of tetrahydrofuran and water (9:1) are added 6.2 g(19 mmol) of cesium carbonate and 2.4 g (7.6 mmol) oftert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate.After sparging with a stream of argon for a few moments, 0.47 mg (0.57mmol) of a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane (PdCl₂(dppf).CH₂Cl₂) is added and the reaction mixtureis refluxed under argon for 5 hours. The mixture is then poured into 250mL of water and the product is extracted with ethyl acetate, the organicphase is dried over sodium sulfate and filtered, and the solvent isevaporated off to give a brown solid. The product is purified bychromatography on silica gel, eluting with a mixture of dichloromethane,methanol and aqueous ammonia (95:5:05) to give 2.91 g of a beige-coloredsolid.

m.p.: 214-216° C.

¹H NMR (CDCl₃) δ: 8.70 (s, 1H), 8.20 (d; 1H), 7.92 (s, 1H), 7.7 (m, 2H),7.3-7.4 (m, 4H), 7.1 (m, 3H), 3.70 (s, 2H), 3.35 (m, 4H), 3.0 (m, 4H),2.70 (m, 4H), 2.70 (s, 3H), 2.35 (s+m, 3+2H), 1.55 (s, 9H) ppm.

Step 6.5.4-[6-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

To a solution of 2.9 g (4.58 mmol) of tert-butyl{4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamatein 30 mL of dichloromethane are added 6.8 mL of trifluoroacetic acid andthe reaction is stirred for 2 hours. The medium is poured into 200 mL ofwater and the mixture is basified by addition of aqueous ammonia.

The organic phase is separated out, dried over sodium sulfate andconcentrated to dryness under reduced pressure. 2.3 g of a white gummysolid are thus isolated.

m.p.: 113° C.

¹H NMR (CDCl₃) δ: 8.10 (d, 1H), 7.70 (m; 2H), 7.3 (m, 4H), 7.1 (pseudot, 2H), 7.00 (d, 1H), 6.90 (s, 1H), 4.40 (broad s, 2H), 3.65 (s, 2H),3.3 (m, 4H), 2.9 (m, 4H), 2.65 (s, 3H), 2.35 (s+m, 3+2H), 1.55 (s, 9H)ppm.

EXAMPLE 7 (Compound 114):4-[2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

To a solution of 2.30 g (4.3 mmol) of4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylaminein 150 mL of methanol are added 4 g (64 mmol) of ammonium formate and 1g of 10% palladium-on-charcoal containing 50% water. The mixture isstirred at reflux for 2 hours and the solvent is then removed underreduced pressure. The residue is taken up in water and the resultingaqueous phase is basified using aqueous 1N sodium hydroxide. The productis extracted with chloroform, the organic phase is washed with water,dried over sodium sulfate and filtered, and the solvent is evaporatedoff to give an orange-colored oil. After purification by chromatographyon a column of silica gel, eluting with a mixture of dichloromethane,methanol and aqueous ammonia (87:13:1.3), 1.23 g of a white powder areobtained after crystallization from ether and drying under reducedpressure.

m.p.: 254-256° C.

¹H NMR (DMSO-d₆) δ: 7.95 (d, 1H), 7.60 (pseudo dd; 2H), 7.20 (pseudo t,2H), 6.65 (s, 1H), 6.65 (d, 1H), 5.95 (broad s, 1H), 3.3 (m, 6H),2.8-3.1 (m, 4H), 2.8-2.25 (m), 2.25 (s, 3H), ppm.

EXAMPLE 8 (Compound 111):4-[2-(4-Chlorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

Synthetic Process According to Scheme 1, Route 1:

Step 8.1. 6-Chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-b]pyridazine(according to Scheme 6)

To a solution, cooled to 0° C., of 3.00 g (11.1 mmol) of6-chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-b]pyridazine (CAS No.:1844-56-0) in 55 mL of chloroform is rapidly added dropwise a solutionof 2.70 g (16.7 mmol) of iodine monochloride in 15 mL of chloroform.After cooling to room temperature and stirring for 3 hours, a further0.75 g (4.6 mmol) of iodine monochloride is added and the reactionmixture is stirred for a further one hour. The mixture is then treatedwith aqueous 5% sodium thiosulfate solution. The product is extractedwith dichloromethane. The organic phase is dried by filtration through ahydrophobic filter cartridge and concentrated under reduced pressure.The residue is triturated in acetonitrile, and the solid is isolated byfiltration. 3.8 g of a beige-colored powder are isolated after dryingunder vacuum.

m.p.: 201-203° C.

¹H NMR (CDCl₃) δ: 8.20 (d; 1H), 8.10 (d, 2H), 8.6 (d, 2H), 7.45 (d, 1H)ppm.

Step 8.2.tert-Butyl{-4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate

To a suspension of 3 g (7.31 mmol) of6-chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-b]pyridazine in 183 mL ofa mixture of tetrahydrofuran and water (9:1) are added 7.1 g (22 mmol)of cesium carbonate and 2.90 g (8.8 mmol) oftert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate.After sparging with a stream of argon for a few moments, 0.54 g (0.66mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) isadded and the reaction mixture is refluxed under argon for 18 hours.After filtering through a Whatman filter and through Celite, thefiltrate is then concentrated under reduced pressure to give 7.0 g of abrown residue. The residue is taken up in water, the product isextracted with dichloromethane, the organic phase is dried over sodiumsulfate and filtered, and the solvent is evaporated off to give 3.5 g ofa dark powder.

The product is purified by chromatography on silica gel, eluting with amixture of dichloromethane and ethyl acetate (100:0 to 80:20) to give1.8 g of beige-colored crystals after crystallization from diisopropylether and drying under reduced pressure.

m.p.: 212-214° C.

¹H NMR (DMSO-d₆) δ: 9.9 (s; 1H), 8.4 (d, 1H), 8.3 (d, 1H), 7.95 (s, 1H),7.60 (d, 2H), 7.45 (m, 3H), 7.15 (d, 1H), 4.40 (s, 9H) ppm.

Step 8.3.4-[6-Chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

To a suspension of 0.76 g (1.67 mmol) of tert-butyl{4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamatein 8 mL of dichloromethane are added 4 mL (48 mmol) of hydrochloricacid. After stirring for 2 hours at room temperature, the solvent isevaporated off under reduced pressure, the oily residue is taken up withaqueous ammonia and the product is extracted with dichloromethane. Theorganic phase is filtered on a hydrophobic cartridge and concentratedunder reduced pressure. The solid obtained is triturated withdiisopropyl ether to give 0.56 g of solid after filtering off and dryingunder reduced pressure.

m.p.: 269-271° C.

¹H NMR (DMSO-d₆) δ: 8.25 (d; 1H), 8.05 (d, 1H), 7.65 (d, 1H), 7.45 (m,3H), 6.65 (m, 2H), 6.1 (broad s, 2H) ppm.

Step 8.4. tert-Butyl5-[3-(2-aminopyrid-4-yl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate

A mixture of 0.15 g (0.42 mmol) of4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamineand 0.36 g (1.7 mmol) of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 7 mL of pentanol isstirred at 135° C. for 20 hours. The solvent is then evaporated offunder reduced pressure and the oily residue is chromatographed on acolumn of silica gel, eluting with a stepwise gradient of methanol andaqueous ammonia in dichloromethane (0:0:100 to 2:1:98). 0.16 g ofproduct is isolated after trituration in diisopropyl ether, filteringoff and drying under reduced pressure.

¹H NMR (DMSO-d₆) δ: 7.95 (d; 1H), 7.85 (d, 1H), 7.55 (d, 2H), 7.40 (d,2H), 6.90 (d, 1H), 6.70 (s, 1H), 6.55 (d, 1H), 5.95 (broad s, 2H),2.9-3.7 (m), 1.35 (s, 9H) ppm.

Step 8.5.4-[2-(4-Chlorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine

To a solution of 0.16 g (0.29 mmol) of tert-butyl5-[3-(2-aminopyrid-4-yl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylatein 3 mL of dichloromethane are added 1.5 mL (18 mmol) of concentratedhydrochloric acid. After stirring for 1 hour at room temperature, thesolvent is evaporated off under reduced pressure, the oily residue istaken up with aqueous ammonia and the product is extracted withdichloromethane. The organic phase is filtered on a hydrophobiccartridge and concentrated under reduced pressure. The solid obtained istriturated with diisopropyl ether to give 0.091 g of solid afterfiltering off and drying under reduced pressure.

m.p.: 267-270° C.

¹H NMR (DMSO-d₆) δ: 7.95 (d; 1H), 7.85 (d, 1H), 7.60 (d, 2H), 7.40 (d,2H), 6.95 (d, 1H), 6.70 (s, 1H), 6.60 (d, 1H), 5.95 (broad s, 2H), 3.6(m, 2H), 3.4-3.1 (m), 2.7-3.95 (m, 4H), 2.6 (d, 2H) ppm.

EXAMPLE 9 (Compound 65):2-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol

Synthesis According to Scheme 1, Route 1:

Step 9.1. 6-Chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazine

To a solution, cooled to 0° C., of 5.20 g (21.0 mmol) of6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS No.:244081-70-7) in 130 mL of chloroform is rapidly added dropwise asolution of 6.61 g (40.9 mmol) of iodine monochloride in 40 mL ofchloroform. After cooling to room temperature and stirring for 4 hours,the mixture is treated with aqueous 5% sodium thiosulfate solution. Theproduct is extracted with dichloromethane. The organic phase is dried byfiltration through a hydrophobic filter cartridge and concentrated underreduced pressure. The residue is triturated in acetonitrile, and thesolid is isolated after filtering off and rinsing with diisopropylether. 5.7 g of a beige-colored powder are isolated after drying undervacuum.

m.p.: 215° C.

¹H NMR (DMSO-d₆) δ: 8.20 (m; 3H), 7.40 (m, 3H) ppm.

Step 9.2.6-Chloro-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine(According to Scheme 6)

To a suspension of 5.7 g (14.8 mmol) of6-chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazine in 370 mL ofa mixture of tetrahydrofuran and water (9:1) are added 14.7 g (44.4mmol) of cesium carbonate and 2.77 g (17.8 mmol) of(2-methoxypyrid-4-yl)boronic acid. After sparging with a stream of argonfor a few moments, 0.98 g (1.2 mmol) of a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane (PdCl₂(dppf).CH₂Cl₂) is added and the reaction mixtureis refluxed under argon for 4 hours. The medium is then concentratedunder reduced pressure to give a black residue. The residue is taken upin 200 mL of water, the product is extracted with 500 mL ofdichloromethane, the organic phase is dried by passing through ahydrophobic filter, filtered and the solvent is evaporated off to give 7g of residue. The product is purified by chromatography on silica gel,eluting with a mixture of dichloromethane and ethyl acetate (100:0 to70:30) to give 3.5 g of beige-colored crystals after crystallizationfrom diisopropyl ether and drying under reduced pressure.

m.p.: 184° C.

¹H NMR (DMSO-d₆) δ: 8.30 (m, 2H), 7.60 (m, 2H), 7.45 (d, 1H), 7.20(pseudo t, 2H), 7.05 (m, 2H), 2.90 (s, 3H) ppm.

Step 9.3.2-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol

A mixture of 0.25 g (0.70 mmol) of6-chloro-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo-[1,2-b]pyridazineand 0.37 g (2.8 mmol) of 2-(piperazin-1-yl)ethanol in 6 mL of pentanolis stirred at 135° C. for 18 hours. The solvent is then evaporated offunder reduced pressure and the oily residue is chromatographed on acolumn of silica gel, eluting with a stepwise gradient of methanol andaqueous ammonia in dichloromethane (0/0/100 to 2/1/98). 0.136 g ofproduct is isolated after trituration in diisopropyl ether, filteringoff and drying under reduced pressure.

m.p.: 176-179° C.

¹H NMR (CDCl₃) δ: 8.20 (d; 1H), 7.80 (d, 1H), 7.60 (d, 2H), 7.00-7.15(m, 4H), 4.00 (s, 3H), 3.70 (m, 2H), 3.55 (m, 4H), 2.7 (m, 6H) ppm.

EXAMPLE 10 (Compound 130):9-[3-(2-Methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane

Synthetic Process According to Scheme 1, Route 1:

Step 10.1. 6-Chloro-2-phenyl-3-iodoimidazo[1,2-b]pyridazine

To a solution, cooled to 0° C., of 10.4 g (45.4 mmol) of6-chloro-2-phenylimidazo[1,2-b]pyridazine (CAS No.: 1844-53-7) in 500 mLof chloroform is rapidly added dropwise a solution of 11.1 g (68.1 mmol)of iodine monochloride in 100 mL of chloroform. After cooling to roomtemperature and stirring for 1 hour, the mixture is treated with aqueous5% sodium thiosulfate solution. The product is extracted withdichloromethane and the organic phase is dried over sodium sulfate andconcentrated under reduced pressure. The residue is triturated in 150 mlof acetonitrile containing a few mL of isopropyl alcohol and the solidis isolated after filtration. 15 g of a yellow powder are isolated afterdrying under vacuum.

m.p.: 207-212° C.

¹H NMR (DMSO-d₅) δ: 8.15 (dd; 2H), 7.90 (d, 1H)), 7.5 (d, 3H)), 7.15 (d,1H) ppm.

Step 10.2.6-Chloro-2-phenyl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine(According to Scheme 6)

To a suspension of 4.33 g (14.8 mmol) of6-chloro-2-phenyl-3-iodoimidazo[1,2-b]pyridazine in 200 mL of a mixtureof tetrahydrofuran and water (9:1) are added 11.9 g (36.5 mmol) ofcesium carbonate and 2 g (14.6 mmol) of (2-methylpyrid-4-yl)boronicacid. After sparging with a stream of argon for a few moments, 0.89 g(1.1 mmol) of a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane (PdCl₂(dppf).CH₂Cl₂) is added and the reaction mixtureis refluxed under argon for 18 hours. The medium is then concentratedunder reduced pressure to give a black residue.

The residue is taken up in 1N hydrochloric acid and the solution isfiltered through a Büchner funnel. The aqueous phase is washed withdiethyl ether and is then basified with aqueous ammonia.

The product is then extracted with dichloromethane and the organic phaseis dried over sodium sulfate and concentrated under reduced pressure togive 3.3 g of a yellowish residue. The product is purified bychromatography on silica gel, eluting with a mixture of dichloromethane,methanol and aqueous ammonia (98/2/0.2)) to give 2.65 g of a pale yellowsolid after drying under reduced pressure.

m.p.: 183-188° C.

¹H NMR (DMSO-d₆) δ: 8.60 (d, 1H), 8.05 (d, 1H), 7.7 (m, 1H), 7.5 (m,5H), 7.20 (d, 1H), 2.60 (s, 3H) ppm.

Step 10.3.9-[3-(2-Methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane

A mixture of 0.80 g (2.5 mmol) of6-chloro-2-phenyl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine and 2.2g (7.5 mmol) of tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate in8 mL of pentanol is stirred at 150° C. for 40 hours.

The mixture is then poured into 30 mL of aqueous 3N hydrochloric acidand stirred for 2 hours. The aqueous phase is washed with diethyl etherand then basified with aqueous ammonia.

The product is then extracted with dichloromethane and the organic phaseis dried over sodium sulfate and concentrated under reduced pressure togive 0.76 g of solid. The product is crystallized from 30 ml ofacetonitrile to give 0.577 g of product after drying under reducedpressure.

m.p.: 175-179° C.

¹H NMR (CDCl₃) δ: 8.50 (d; 1H), 7.75 (d, 1H), 7.65 (m, 2H), 7.50 (s,1H), 7.30-7.45 (m, 4H), 6.90 (d, 1H), 3.50 (t, 4H), 2.85 (m, 2H), 2.75(s, 2H), 2.55 (s, 3H), 1.6-1.75 (m, 6H) ppm.

EXAMPLE 11 (Compound 147):2-Phenyl-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine

Synthetic Process According to Scheme 1, Route 2:

Step 11.1. 2-Bromo-1-phenyl-2-pyrid-4-ylethanone

To a solution of 36 g (182 mmol) of 1-phenyl-2-pyrid-4-ylethanone in 350mL of acetic acid are successively added at room temperature 28 ml (210mmol) of a solution containing 30% by weight of hydrobromic acid inacetic acid and 10.1 ml (197 mmol) of bromine dissolved in 50 mL ofacetic acid. The solution is heated at 60° C. for one hour and thencooled. The product is precipitated by adding diethyl ether, and 63 g ofa yellow solid are isolated after drying.

¹H NMR (DMSO-d₆) δ: 8.80 (d; 2H), 8.10 (d, 2H), 7.90 (d, 2H), 7.70 (m,1H), 7.60 (m, 2H), 7.25 (s, 1H) ppm.

Step 11.2. 6-Chloro-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine

A mixture of 13 g (36.5 mmol) of 2-bromo-1-phenyl-2-pyrid-4-ylethanone(CAS No.: 741633-76-1) and 18.9 g (146 mmol) of6-chloropyridazin-3-ylamine in 200 mL of ethanol is maintained at 90° C.for 5 hours 30 minutes. After cooling, the solvent is evaporated offunder reduced pressure, the medium is taken up in 50 mL of water and theproduct is extracted with ethyl acetate. The organic phases are driedover magnesium sulfate and then concentrated under reduced pressure.

The solid obtained is recrystallized from 50 mL of methanol to give 4.0g of yellow crystals after drying.

¹H NMR (CDCl₃) δ: 8.80 (d, 2H), 8.10 (d, 1H), 7.55-7.80 (m, 4H), 7.50(m, 2H), 7.35 (s, 1H), 7.20 (d, 1H) ppm.

Step 11.3.2-Phenyl-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine

A mixture of 4.03 g (13.1 mmol) of6-chloro-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine and 4.4 g (29mmol) of 4-pyrrolidin-1-ylpiperidine in 50 mL of ethanol is heated at155° C. for 4 hours. After cooling, the solvent is evaporated off underreduced pressure and the residue is chromatographed on silica gel,eluting with a mixture of dichloromethane and methanol (93:7).

The product is then recrystallized from 40 mL of methanol to give 1.5 gof yellow crystals after drying under reduced pressure.

m.p.: 165.0-165.5° C.

¹H NMR (CDCl₃) δ: 8.65 (d; 2H), 7.80 (d, 1H), 7.65 (m, 4H), 7.35 (m,3H), 6.95 (d, 1H), 4.10 (m, 2H), 3.00 (m, 2H), 2.60 (m, 4H), 2.55 (m,1H), 2.05 (m, 2H), 1.85 (m, 4H), 1.65 (m, 2H) ppm.

BIOLOGICAL EXAMPLES

The capacity of the compounds of the invention to inhibit thephosphorylation of casein by casein kinases 1 epsilon and delta may beevaluated according to the procedure described in document US 2005/0 131012.

Filter-Plate Assay of ATP-³³P for the Screening of CK1 EpsilonInhibitors:

The effect of the compounds on inhibition of the phosphorylation ofcasein by the enzyme casein kinase 1 epsilon (CK1 epsilon) is measured,using a casein assay via filtration of ATP-³³P in vitro.

Casein kinase 1 epsilon (0.58 mg/ml) is obtained via fermentation andpurification processes performed according to methods that are wellknown to those skilled in the art, or may also be obtained fromInvitrogen Corporation™ (human CK1 epsilon).

The compounds are tested at five different concentrations so as togenerate IC₅₀ values, i.e. the concentration at which a compound iscapable of inhibiting the enzymatic activity by 50%, or alternativelythe percentage of inhibition at a concentration of 10 micromolar.

“U”-bottomed Falcon plates are prepared by placing 5 μL of solutions ofthe compounds according to the invention at concentrations of 10, 1,0.1, 0.01 or 0.001 μM in different wells. The solutions of the compoundsaccording to the invention at these various concentrations are preparedby diluting in a test buffer (Tris 50 mM pH 7.5, MgCl₂ 10 M, DTT 2 mMand EGTA 1 mM) a stock solution in DMSO at a concentration of 10 mM.Next, 5 μL of dephosphorylated casein are added to a final concentrationof 0.2 ng/μL, 20 μL of CK1 epsilon to a final concentration of 3 μg/μL,and 20 μL of ATP-³³P to a final concentration of 0.02 μCi/μL mixed withcold ATP (10 μM final—approximately 2 10⁶ CPM per well). The final totaltest volume per well is equal to 50 μL.

The “U”-bottomed Falcon® test plate mentioned above is vortexed, andthen incubated at room temperature for 2 hours. After 2 hours thereaction is stopped by adding an ice-cold solution of 65 μL of cold ATP(2 mM) prepared in test buffer.

100 μL of the reaction mixture are then transferred from the“U”-bottomed Falcon® plate into Millipore® MAPH filter plates,preimpregnated with 25 μL of ice-cold 100% TCA.

The Millipore MAPH filter plates are agitated gently and are left tostand at room temperature for at least 30 minutes to precipitate theproteins.

After 30 minutes, the filter plates are sequentially washed and filteredwith 2 150 μL of 20% TCA, 2 150 μL of 10% TCA and 2 150 μL of 5% TCA (6washes in total per plate/900 μL per well).

The plates are left to dry overnight at room temperature. Next, 40 μL ofMicroscint-20 Packard® scintillation liquid are added per well and theplates are closed in a leak tight manner. The radiation emitted by eachwell is then measured for 2 minutes in a TopCount NXT Packard®scintillation counter, in which the values of CPM/well are measured.

The percentage inhibition of the capacity of the enzyme to phosphorylatethe substrate (casein) is determined for each concentration of testcompound. These inhibition data expressed as percentages are used tocalculate the IC₅₀ value for each compound compared with the controls.

The kinetic studies determined the K_(M) value for ATP as being 21 μM inthis test system. Under these conditions, the compounds of the inventionthat are the most active have IC₅₀ values (concentrations that inhibit50% of the enzymatic activity of casein kinase 1 epsilon or caseinkinase 1 delta) of between 1 nM and 200 nM.

Table 2 below gives the IC₅₀ values for the inhibition ofphosphorylation of casein kinase 1 epsilon for a number of compoundsaccording to the invention.

TABLE 2 Compound CK1 epsilon IC₅₀ (nM) 1 3 3 1 30 60  147 22-116 153 8

The capacity of the compounds of the invention to inhibit thephosphorylation of casein by the casein kinases 1 epsilon and delta maybe evaluated using an FRET (Fluorescence Resonance Energy Transfer)fluorescence test with the aid of the “Z′Lyte™ kinase assay kit”(reference PV3670; Invitrogen Corporation™) according to themanufacturer's instructions.

The casein kinases 1 used are obtained from Invitrogen Corporation(human CK1 epsilon PV3500 and human CK1 delta PV3665).

A peptide substrate, labeled at both ends with a fluorophore-donatinggroup (coumarin) and a fluorophore-accepting group (fluorescein)constituting an FRET system is dephosphorylated in the presence of ATPby casein kinase 1 epsilon or delta in the presence of increasingconcentrations of compounds of the invention.

The mixture is treated with a site-specific protease that specificallycleaves the substrate peptide to form two fluorescent fragments having alarge fluorescence emission ratio.

The fluorescence observed is thus related to the capacity of theproducts of the invention to inhibit the phosphorylation of thesubstrate peptide by casein kinase 1 epsilon or casein kinase 1 delta.

The compounds of the invention are dissolved at different concentrationsstarting with a 10 mM stock solution in DMSO diluted in a buffercontaining 50 mM HEPS, pH 7.5, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCl₂ forcasein kinase 1 epsilon and supplemented with Trizma Base (50 mM), pH8.0 and NaN₃ (0.01% final) for casein kinase 1 delta.

The phosphorylation of the substrate peptide SER/THR 11 obtained fromInvitrogen Corporation™ is performed at a final concentration of 2 μM.The ATP concentration is 4 times the K_(M), this value being 2 μM forcasein kinase 1 epsilon and 4 μM for casein kinase 1 delta.

The emitted fluorescence is measured at wavelengths of 445 and 520 nm(excitation at 400 nm). Under these conditions, the compounds of theinvention that are the most active have IC₅₀ values (concentration thatinhibits 50% of the enzymatic activity of casein kinase 1 epsilon orcasein kinase 1 delta) of between 1 nM and 200 nM.

Table 3 below gives the IC₅₀ values for the inhibition ofphosphorylation of casein kinase 1 delta for a number of compoundsaccording to the invention.

TABLE 3 Compound CK1 delta IC₅₀ (nM) 31 91-93 50 5 81  59-110 147 50-53

It is thus seen that the compounds according to the invention haveinhibitory activity on the enzyme casein kinase 1 epsilon or caseinkinase 1 delta.

Experimental Protocols for Circadian Cell Assay

Mper1-luc Rat-1 (P2C4) fibroblast cultures were prepared by dividing thecultures every 3-4 days (about 10-20% of confluence) on 150 cm² degassedpolystyrene tissue culture flasks (Falcon® #35-5001) and maintained ingrowth medium [EMEM (Cellgro #10-010-CV); 10% fetal bovine serum (FBS;Gibco #16000-044); and 50 I.U./mL of penicillin-streptomycin (Cellgro#30-001-CI)] at 37° C. and under 5% CO₂.

Cells obtained from Rat-1 fibroblast cultures at 30-50% of confluence asdescribed above were co-transfected with vectors containing theselection marker for resistance to zeocin for a stable transfection anda luciferase reporter gene directed by the promoter mPer-1. After 24 to48 hours, the cultures were divided on 96-well plates and maintained ingrowth medium supplemented with 50-100 μg/mL of zeocin (Invitrogen®#45-0430) for 10-14 days. The zeocin-resistant stable transfectants wereevaluated for expression of the reporter by adding to the growth mediumluciferin 100 μM (Promega® #E1603®) and by assaying the luciferaseactivity on a TopCount® scintillation counter (Packard model #C384V00).The Rat-1 cell clones expressing both zeocin resistance and luciferaseactivity directed by mPer1 were serum-shock synchronized with 50% horseserum [HS (Gibco® #16050-122)] and the activity of the circadianreporter was evaluated. The P2C4 clone of fibroblasts Mper1-luc Rat-1was selected to test the compound.

The Mper1-luc Rat-1 (P2C4) fibroblasts at 40-50% of confluence obtainedaccording to the protocol described above were plated out onto 96-wellopaque tissue culture plates (Perkin Elmer® #6005680). The cultures aremaintained in growth medium supplemented with 100 μg/mL of zeocin(Invitrogen #45-0430) until they reached 100% of confluence (48-72hours). The cultures were then synchronized with 100 μL ofsynchronization medium [EMEM (Cellgro #10-010-CV); 100 I.U./mL ofpenicillin-streptomycin (Cellgro #30-001-C1); 50% HS (Gibco #16050-122)]for 2 hours at 37° C. and under 5% CO₂. After synchronization, thecultures were rinsed with 100 μL of EMEM (Cellgro #10-010-CV) for 10minutes at room temperature. After rinsing, the medium is replaced with300 μL of CO₂-independent medium [CO₂I (Gibco #18045-088); L-glutamine 2mM (Cellgro #25-005-C1); 100 I.U./mL of penicillin-streptomycin (Cellgro#30-001-C1); luciferin 100 μM (Promega #E 1603)]. The compounds of theinvention tested for the circadian effects were added to CO₂-independentmedium in DMSO at 0.3% (final concentration). The cultures wereimmediately closed in a leak tight manner with TopSeal-A® film (Packard#6005185) and transferred for the luciferase activity measurement.

After synchronization, the test plates were maintained at 37° C. in atissue culture oven (Form a Scientific Model #3914). The in vivoluciferase activity was estimated by measuring the relative lightemission on a TopCount scintillation counter (Packard model #C384V00).

The period analysis was performed either by determining the intervalbetween the relative light emission minima over several days or byFourier transform.

The two methods produced a virtually identical period estimation on arange of circadian periods. The power is given in CE Delta (t+1 h),which is presented as the effective micromolar concentration that inducea 1-hour prolongation of the period. The data were analyzed by adjustinga hyperbolic curve to the data expressed as change of period (y-axis) asa function of the concentration of the test compound (x-axis) in theXLfit™ software and the CE Delta (t+1 h) was interpolated from thiscurve.

Table 4 below gives the CE Delta (t+1 h) for a number of compoundsaccording to the invention.

TABLE 4 Compound CE Delta (t + 1 h) (nM) 50 28 115  2 146 39 153 2-9

By inhibiting the enzymes CK1 epsilon and/or CK1 delta, the compoundsthat are the subject of the invention modulate the circadianperiodicity, and may be useful for treating circadian rhythm disorders.

The compounds according to the invention may especially be used for thepreparation of a medicament for preventing or treating sleep disorders;circadian rhythm disorders, especially such as those caused by jetlag orshift work.

Among the sleep disorders that are especially distinguished are primarysleep disorders such as dyssomnia (for example primary insomnia),parasomnia, hypersomnia (for example excessive somnolence), narcolepsy,sleep disorders related to sleep apnea, sleep disorders related to thecircadian rhythm and other unspecified dyssomnias, sleep disordersassociated with medical/psychiatric disorders.

The compounds that are the subject of the invention also cause acircadian phase shift and such a property may be useful in the contextof a potential monotherapy or combined therapy that is clinicallyeffective in the case of mood disorders.

Among the mood disorders that are especially distinguished aredepressive disorders (unipolar depression), bipolar disorders, mooddisorders caused by a general medical complaint and also mood disordersinduced by pharmacological substances. Among the bipolar disorders thatare especially distinguished are bipolar I disorders and bipolar IIdisorders, especially including seasonal affective disorders.

The compounds that are the subject of the invention, which modulate thecircadian periodicity, may be useful in the treatment of anxiety anddepressive disorders caused in particular by an impairment in thesecretion of CRF.

Among the depressive disorders that are especially distinguished aremajor depressive disorders, dysthymic disorders and other unspecifieddepressive disorders.

The compounds that are the subject of the invention, which modulate thecircadian periodicity, may be useful for preparing a medicament fortreating diseases related to dependency on abuse substances such ascocaine, morphine, nicotine, ethanol and cannabis.

By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, thecompounds according to the invention may be used for preparingmedicaments, especially for preparing a medicament for preventing ortreating diseases related to hyperphosphorylation of the tau protein,especially Alzheimer's disease.

These medicaments also find their use in therapy, especially in thetreatment or prevention of diseases caused or exacerbated by theproliferation of cells and in particular of tumor cells.

As tumor cell proliferation inhibitors, these compounds are useful inthe prevention and treatment of liquid tumors such as leukemias, solidtumors that are both primary and metastatic, carcinomas and cancers, inparticular: breast cancer; lung cancer; small intestine cancer andcolorectal cancer; cancer of the respiratory pathways, of the oropharynxand of the hypopharynx; cancer of the esophagus; liver cancer, stomachcancer, cancer of the bile ducts, cancer of the bile vesicle, pancreaticcancer; cancers of the urinary pathways including the kidney, urotheliumand bladder; cancers of the female genital tract, including cancer ofthe uterus, of the cervix, of the ovaries, choriocarcinoma andtrophoblastoma; cancers of the male genital tract, including cancer ofthe prostate, of the seminal vesicles, of the testicles and germinalcell tumors; cancers of the endocrine glands, including cancer of thethyroid, of the pituitary and of the adrenal glands; skin cancersincluding hemiangiomas, melanomas and sarcomas, including Kaposi'ssarcoma; brain, nerve, eye or meningeal tumors, including astrocytomas,gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas,schwannomas and meningiomas; malignant hematopoietic tumors; leukemias(Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), ChronicMyeloid Leukemia (CML), Chronic lymphocytic leukemia (CLL)) chloromas,plasmocytomas, T or B cell leukemias, Hodgkin or non-Hodgkin lymphomas,myelomas and various malignant hemopathies.

The compounds according to the invention may thus be used for thepreparation of medicaments, in particular of medicaments for inhibitingcasein kinase 1 epsilon and/or casein kinase 1 delta.

Thus, according to another of its aspects, a subject of the invention ismedicaments comprising a compound of formula (I), or an addition saltthereof with a pharmaceutically acceptable acid, or alternatively ahydrate or solvate of the compounds of formula (I).

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention or apharmaceutically acceptable salt, a hydrate or solvate of said compound,and also at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and thedesired mode of administration, from the usual excipients known to thoseskilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the possible salt, solvate orhydrate thereof, may be administered in unit administration form, as amixture with standard pharmaceutical excipients, to man and animals forthe prophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms include oral-route forms suchas tablets, soft or hard gel capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal, intraocularand intranasal administration forms, inhalation forms, topical,transdermal, subcutaneous, intramuscular or intravenous administrationforms, rectal administration forms and implants. For topicaladministration, the compounds according to the invention may be used increams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

Via the oral route, the dose of active principle administered per daymay range from 0.1 to 20 mg/kg, in one or more dosage intakes.

There may be particular cases in which higher or lower dosages areappropriate; such dosages are not outside the context of the invention.According to the usual practice, the dosage that is appropriate to eachpatient is determined by the practitioner according to the mode ofadministration and the weight and response of said patient.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration to a patient of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt or hydrate or solvate thereof.

What is claimed is:
 1. A process for preparing a compound of formula(I),

or salt thereof, which comprises reacting a compound of formula (IIa):

with an amine of formula (IIIa):

in a polar solvent wherein X6 is a leaving group; R₂ represents an arylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ fluoroalkyl, C₁₋₆-fluoroalkyloxy and —CN; R₃ representsa hydrogen atom, C₁₋₃ alkyl, —NR₄R₅, hydroxyl or C₁₋₄ alkyloxy; Arepresents a group C₁₋₇-alkylene optionally substituted with one or twogroups R_(a); B represents a group C₁₋₇-alkylene optionally substitutedwith a group R_(b); L represents either a nitrogen atom substituted witha group R_(c) or R_(d), or a carbon atom substituted with a group R_(e1)and a group R_(d) or two groups R_(e2); the carbon atoms of A and Bbeing optionally substituted with one or more groups R_(f), which may beidentical to or different than each other; R_(a), R_(b) and R_(c) aredefined such that: two groups R_(a) may together form a groupC₁₋₆-alkylene; R_(a) and R_(b) may together form a bond or a groupC₁₋₆-alkylene; R_(a) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(b) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(d) represents a group selected from the groupconsisting of a hydrogen atom and the groups C₁₋₆-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, C₁₋₆-alkyl, C₁₋₆-alkylthio,C₁₋₆-alkyl, C₁₋₆-alkyloxy, C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl,C₁₋₆-acyl and hydroxy-C₁₋₆-alkyl; R_(e1) represents a group —NR₄R₅ or acyclic monoamine optionally comprising an oxygen atom, the cyclicmonoamine being optionally substituted with one or more substituentsselected from the group consisting of a fluorine atom and the groupsC₁₋₆-alkyl, C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2) form, with thecarbon atom that bears them, a cyclic monoamine optionally comprising anoxygen atom, this cyclic monoamine being optionally substituted with oneor more groups R_(f), which may be identical to or different than eachother; R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or benzyl; R₄ and R₅ represent,independently of each other, a hydrogen atom or a group C₁₋₄ alkyl,C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent,independently of each other, a hydrogen atom or a group C₁₋₆-alkyl.
 2. Aprocess for preparing a compound of formula (I),

or salt thereof which comprises reacting a compound of formula (Vb):

with a compound of formula (VIb):

in a polar solvent, wherein R₂ represents an aryl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio,C₁₋₆ fluoroalkyl, C₁₋₆-fluoroalkyloxy and —CN; R₃ represents a hydrogenatom, C₁₋₃ alkyl, —NR₄R₅, hydroxyl or C₁₋₄ alkyloxy; A represents agroup C₁₋₇-alkylene optionally substituted with one or two groups R_(a);B represents a group C₁₋₇-alkylene optionally substituted with a groupR_(b); L represents either a nitrogen atom substituted with a groupR_(c) or R_(d), or a carbon atom substituted with a group R_(e1) and agroup R_(d) or two groups R_(e2); the carbon atoms of A and B beingoptionally substituted with one or more groups R_(f), which may beidentical to or different than each other; R_(a), R_(b) and R_(c) aredefined such that: two groups R_(a) may together form a groupC₁₋₆-alkylene; R_(a) and R_(b) may together form a bond or a groupC₁₋₆-alkylene; R_(a) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(b) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(d) represents a group selected from the groupconsisting of a hydrogen atom and the groups C₁₋₆-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl, C₁₋₆-acyl andhydroxy-C₁₋₆-alkyl; R_(e1) represents a group —NR₄R₅ or a cyclicmonoamine optionally comprising an oxygen atom, the cyclic monoaminebeing optionally substituted with one or more substituents selected fromthe group consisting of a fluorine atom and the groups C₁₋₆-alkyl,C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2) form, with the carbon atomthat bears them, a cyclic monoamine optionally comprising an oxygenatom, this cyclic monoamine being optionally substituted with one ormore groups R_(f), which may be identical to or different than eachother; R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or benzyl; R₄ and R₅ represent,independently of each other, a hydrogen atom or a group C₁₋₄ alkyl,C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent,independently of each other, a hydrogen atom or a group C₁₋₆-alkyl.
 3. Aprocess for preparing a compound of formula (I)

or salt thereof comprising: reacting a compound of formula (IId):

with a compound of formula (IVd):

in the presence of a catalyst and a mineral base, and in a polar aproticsolvent wherein X is an iodine atom; R₂ represents an aryl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ fluoroalkyl, C₁₋₆-fluoroalkyloxy and —CN; R₃ representsa hydrogen atom, C₁₋₃ alkyl, —NR₄R₅, hydroxyl or C₁₋₄ alkyloxy; Arepresents a group C₁₋₇-alkylene optionally substituted with one or twogroups R_(a); B represents a group C₁₋₇-alkylene optionally substitutedwith a group R_(b); L represents either a nitrogen atom substituted witha group R_(c) or R_(d), or a carbon atom substituted with a group R_(e1)and a group R_(d) or two groups R_(e2); the carbon atoms of A and Bbeing optionally substituted with one or more groups R_(f), which may beidentical to or different than each other; R_(a), R_(b) and R_(c) aredefined such that: two groups R_(a) may together form a groupC₁₋₆-alkylene; R_(a) and R_(b) may together form a bond or a groupC₁₋₆-alkylene; R_(a) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(b) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(d) represents a group selected from the groupconsisting of a hydrogen atom and the groups C₁₋₆-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl, C₁₋₆-acyl andhydroxy-C₁₋₆-alkyl, R_(e1) represents a group —NR₄R₅ or a cyclicmonoamine optionally comprising an oxygen atom, the cyclic monoaminebeing optionally substituted with one or more substituents selected fromthe group consisting of a fluorine atom and the groups C₁₋₆-alkyl,C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2) form, with the carbon atomthat bears them, a cyclic monoamine optionally comprising an oxygenatom, this cyclic monoamine being optionally substituted with one ormore groups R_(f), which may be identical to or different than eachother R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or benzyl; R₄ and R₅ represent,independently of each other, a hydrogen atom or a group C₁₋₄ alkyl,C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent,independently of each other, a hydrogen atom or a group C₁₋₆-alkyl.
 4. Aprocess for preparing a compound of formula (I)

or salt thereof comprising: reacting a compound of formula (IIc):

with a compound of formula (IVc):

wherein M represents a trialkylstannyl group or a dihydroxyboryl ordialkyloxyboryl group; X represents an iodine or bromine atom; R₂represents an aryl group optionally substituted with one or moresubstituents selected from the group consisting of halogen atoms, C₁₋₆alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ fluoroalkyl,C₁₋₆-fluoroalkyloxy and —CN; R₃ represents a hydrogen atom, C₁₋₃ alkyl,—NR₄R₅, hydroxyl or C₁₋₄ alkyloxy; A represents a group C₁₋₇-alkyleneoptionally substituted with one or two groups R_(a); B represents agroup C₁₋₇-alkylene optionally substituted with a group R_(b); Lrepresents either a nitrogen atom substituted with a group R_(c) orR_(d), or a carbon atom substituted with a group R_(e1) and a groupR_(d) or two groups R_(e2); the carbon atoms of A and B being optionallysubstituted with one or more groups R_(f), which may be identical to ordifferent than each other; R_(a), R_(b) and R_(c) are defined such that:two groups R_(a) may together form a group C₁₋₆-alkylene; R_(a) andR_(b) may together form a bond or a group C₁₋₆-alkylene; R_(a) and R_(c)may together form a bond or a group C₁₋₆-alkylene; R_(b) and R_(c) maytogether form a bond or a group C₁₋₆-alkylene; R_(d) represents a groupselected from the group consisting of a hydrogen atom and the groupsC₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl,C₁₋₆-alkylthio-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl,benzyl, C₁₋₆-acyl and hydroxy-C₁₋₆-alkyl; R_(e1) represents a group—NR₄R₅ or a cyclic monoamine optionally comprising an oxygen atom, thecyclic monoamine being optionally substituted with one or moresubstituents selected from the group consisting of a fluorine atom andthe groups C₁₋₆-alkyl, C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2)form, with the carbon atom that bears them, a cyclic monoamineoptionally comprising an oxygen atom, this cyclic monoamine beingoptionally substituted with one or more groups R_(f), which may beidentical to or different than each other; R_(f) represents a groupC₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl orbenzyl; R₄ and R₅ represent, independently of each other, a hydrogenatom or a group C₁₋₄ alkyl, C₃₋₇-cycloalkyl orC₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent, independently ofeach other, a hydrogen atom or a group C₁₋₆-alkyl.
 5. A process forpreparing a compound of formula (I) or salt thereof

or salt thereof comprising: a) reacting a compound of formula (IId):

with a compound of formula (IVe):

in the presence of an alkyl chloroformate, to obtain a compound offormula (IIe):

and b) reacting the product of formula (IIe) obtained in step a) with anoxidizing agent to obtain a compound of formula (I) in which R₃represents a hydrogen atom or a group C₁₋₃-alkyl, R₂ represents an arylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen atom, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆-fluoroalkyl, C₁₋₆-fluoroalkyloxy and —CN; A represents agroup C₁₋₇-alkylene optionally substituted with one or two groups R_(a);B represents a group C₁₋₇-alkylene optionally substituted with a groupR_(b); L represents either a nitrogen atom substituted with a groupR_(c) or R_(d), or a carbon atom substituted with a group R_(e1) and agroup R_(d) or two groups R_(e2); the carbon atoms of A and B beingoptionally substituted with one or more groups R_(f), which may beidentical to or different than each other; R_(a), R_(b) and R_(c) aredefined such that: two groups R_(a) may together form a groupC₁₋₆-alkylene; R_(a) and R_(b) may together form a bond or a groupC₁₋₆-alkylene; R_(a) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(b) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(d) represents a group selected from the groupconsisting of a hydrogen atom and the groups C₁₋₆-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl, C₁₋₆-acyl andhydroxy-C₁₋₆-alkyl, R_(e1) represents a group —NR₄R₅ or a cyclicmonoamine optionally comprising an oxygen atom, the cyclic monoaminebeing optionally substituted with one or more substituents selected fromthe group consisting of a fluorine atom and the groups C₁₋₆-alkyl,C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2) form, with the carbon atomthat bears them, a cyclic monoamine optionally comprising an oxygenatom, this cyclic monoamine being optionally substituted with one ormore groups R_(f), which may be identical to or different than eachother; R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or benzyl; R₄ and R₅ represent,independently of each other, a hydrogen atom or a group C₁₋₄ alkyl,C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent,independently of each other, a hydrogen atom or a group C₁₋₆-alkyl; or asalt thereof.
 6. A method for treating a circadian rhythm disorder in apatient comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein R₂ represents anaryl group optionally substituted with one or more substituents selectedfrom the group consisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkyloxy,C₁₋₆ alkylthio, C₁₋₈ fluoroalkyl, C₁₋₆-fluoroalkyloxy and —CN; R₃represents a hydrogen atom, C₁₋₃ alkyl, —NR₄R₅, hydroxyl or C₁₋₄alkyloxy; A represents a group C₁₋₇-alkylene optionally substituted withone or two groups R_(a); B represents a group C₁₋₇-alkylene optionallysubstituted with a group R_(b); L represents either a nitrogen atomsubstituted with a group R_(c) or R_(d), or a carbon atom substitutedwith a group R_(e1) and a group R_(d) or two groups R_(e2); the carbonatoms of A and B being optionally substituted with one or more groupsR_(f), which may be identical to or different than each other; R_(a),R_(b) and R_(c) are defined such that: two groups R_(a) may togetherform a group C₁₋₆-alkylene; R_(a) and R_(b) may together form a bond ora group C₁₋₆-alkylene; R_(a) and R_(c) may together form a bond or agroup C₁₋₆-alkylene; R_(b) and R_(c) may together form a bond or a groupC₁₋₆-alkylene; R_(d) represents a group selected from the groupconsisting of a hydrogen atom and the groups C₁₋₆-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl, benzyl, C₁₋₆-alkylC(O) andhydroxy-C₁₋₆-alkyl; R_(e1) represents a group —NR₄R₅ or pyrrolidinyl ormorpholinyl, optionally substituted with one or more substituentsselected from the group consisting of a fluorine atom and the groupsfluoro C₁₋₆-alkyl, C₁₋₆-alkyloxy and hydroxyl; two groups R_(e2) form,with the carbon atom that bears them, a cyclic monoamine optionallycomprising an oxygen atom, this cyclic monoamine being pyrrolidinyl,piperidinyl, or morpholinyl optionally substituted with one or moregroups R_(f), which may be identical to or different than each other;R_(f) represents a group C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, C₁₋₆-fluoroalkyl or benzyl; R₄ and R₅ represent,independently of each other, a hydrogen atom or a group C₁₋₄ alkyl,C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyl-C₁₋₆-alkyl; and R₇ and R₈ represent,independently of each other, a hydrogen atom or a group C₁₋₆-alkyl. 7.The method for treating a circadian rhythm disorder in a patientaccording to claim 6 wherein the compound is selected from the groupconsisting of:2-Phenyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-7,8-dimethyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;4-[2-(4-Fluorophenyl)-6-piperazin-1-ylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;2-(4-Chlorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Chlorophenyl)-7-methyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Chlorophenyl)-8-methyl-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dimethylphenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Difluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Difluorophenyl)-3-(2-methylpyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;2-(3,4-Difluorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dichlorophenyl)-6-piperazin-1-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dichlorophenyl)-3-(2-methylpyrid-4-yl)-6-piperazin-1-ylimidazo[1,2-b]pyridazine;(±)-6-(3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((R)-3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((R)-3-Methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;6-((S)-3-Methylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3-Fluorophenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-((S)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-((R)-3-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine;2-(3,4-Difluorophenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(3,3-Dimethylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;4-[2-(3,5-Dimethylphenyl)-6-(3,3-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;4-[2-(3,5-Difluorophenyl)-6-(3,3-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;2-(3,5-Dichlorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dichlorophenyl)-6-(3,3-dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;(±)-6-(3,4-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-(3,5-Dimethylphenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,4-Difluorophenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Chlorophenyl)-6-((cis)-3,5-dimethylpiperazin-1-yl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((cis)-3,5-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(2-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Chlorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,4-Difluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3-Methoxyphenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Methoxyphenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(4-Methylpiperazin-1-yl)-3-pyrid-4-yl-2-p-tolylimidazo[1,2-b]pyridazine;6-(4-Methylpiperazin-1-yl)-3-pyrid-4-yl-2-(4-trifluoromethylphenyl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;{4-[2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}dimethylamine;2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine;6-(4-Ethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3,5-Dimethylphenyl)-6-(4-ethylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-[4-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl]ethanol;2-{4-[2-(3-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[2-(3,4-Difluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[2-(4-Chlorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[3-(2-Aminopyrid-4-yl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-(4-Chlorophenyl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-[4-(2-Fluoroethyl)piperazin-1-yl]-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-[4-(2-Fluoroethyl)piperazin-1-yl]-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-Phenyl-3-pyrid-4-yl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-pyrid-4-yl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]imidazo[1,2-b]pyridazine;6-(4-Cyclopropylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(4-Cyclopropylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;6-(4-Isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;2-(3-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-(3,4-Difluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;4-[2-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;2-Methyl-1-[4-(2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl]propan-2-ol;1-{4-[2-(3-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;1-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;6-(4-Butylpiperazin-1-yl)-2-(4-chlorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;4-{4-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylbutan-2-ol;6-(4-Cyclohexylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;1-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanone;1-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-1-one;(±)-2-(4-Fluorophenyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl-3-(2-methoxypyrid-1-4-yl)imidazo[1,2-b]pyridazine;6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-{(1S,4S)-5-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethanol;2-(4-Fluorophenyl)-6-(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-methyl[1,4]diazepan-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-3-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]octahydro(1H)pyrrolo[1,2-d][1,4]diazepine;(±)-4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-1,4-diazabicyclo[3.2.2]nonane;(±)-4-[2-(3,5-Dimethylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-1,4-diazabicyclo[3.2.2]nonane;(±)-3,6-diazabicyclo[3.2.0]hept-3-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;6-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazine;2-(3-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;4-[2-(4-Chlorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;4-[6-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-7,8-dimethyl-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;4-[2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;6-(5-Cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2-(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine(±)-6-(Octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-3-(2-Methylpyrid-4-yl)-6-(octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl)-2-phenylimidazo[1,2-b]pyridazine;(±)-(cis)-2-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]decahydro[2,6]-naphthyridine;(±)-6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(3-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(2,8-Diazaspiro[4.5]dec-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(2,7-Diazaspiro[4.5]dec-2-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(2,8-Diazaspiro[4.5]dec-8-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(2,7-Diazaspiro[4.5]dec-7-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;3-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-3,9-diazaspiro[5.5]undecane;9-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)-2,9-diazaspiro[5.5]undecane;9-[3-(2-Methylpyrid-4-yl)-2-phenylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;9-[2-(3-Fluorophenyl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;9-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;9-[2-(4-Fluorophenyl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;4-[2-(4-Chlorophenyl)-6-(2,9-diazaspiro[5.5]undec-9-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine;9-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro-[5.5]undecane;2-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane2-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,8-diazaspiro[5.5]undecane9-[2-(phenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane;9-[2-(4-Fluorophenyl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane;9-[2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane;4-{[2-(4-Chlorophenyl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-2-ylamine;(±)-{1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl}dimethylamine;2-(3,5-Dimethylphenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;6-(4-Morpholin-4-ylpiperid-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-[4-(2,6-Dimethylmorpholin-4-yl)piperid-1-yl]-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;{1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperid-4-yl}dimethylamine;2-Phenyl-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazine;(R)-1-{1-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperid-4-yl}pyrrolidin-3-ol;6-(4-Morpholin-4-ylpiperid-1-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(3-Fluoro-5-methylphenyl)-6-((R)-3-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo-[1,2-b]pyridazine;{4-[2-(4-Fluorophenyl)-6-((R)-3-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-7-methyl-3-pyrid-4-ylimidazo-[1,2-b]pyridazine;6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo-[1,2-b]pyridazine;6-(3,3-Dimethylpiperazin-1-yl)-2-(3-fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo-[1,2-b]pyridazine;{4-[6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;6-((R)-3-Ethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(3,3-Diethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(3-Fluoromethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-{(4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-2-yl}methanol;2-{4-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;2-{4-[2-(4-Fluorophenyl)-3-(2-methylaminopyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-piperazin-1-yl}ethanol;1-{4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;1-{4-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;1-{4-[2-(4-Fluorophenyl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;1-{4-[2-(4-Fluorophenyl)-3-(2-methylaminopyrid-4-yl)imidazo[1,2-b]pyridazin-6-yl]-piperazin-1-yl}-2-methylpropan-2-ol;2-{(R)-4-[2-(4-Fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]piperazin-2-yl}propan-2-ol;2-(4-Fluorophenyl)-6-((R)-3-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]-pyridazine;{4-[2-(4-Fluorophenyl)-6-((R)-3-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;2-(3-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)imidazo-[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-7-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;{4-[2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-pyrid-2-yl}methylamine;2-(3,4-Difluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methoxypyrid-4-yl)imidazo[1,2-b]pyridazine;2-(3-Fluoro-5-methylphenyl)-6-(4-isopropylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-6-(3,6-Diazabicyclo[3.2.0]hept-3-yl)-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;{4-[(1S,4S)-6-2,5-Diazabicyclo[2.2.1]hept-2-yl-2-(4-fluorophenyl)imidazo[1,2-b]-pyridazin-3-yl]pyrid-2-yl}methylamine;2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-7-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-8-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;2-Methyl-1-[(1S,4S)-5-(2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]propan-2-ol;6-(3,6-Diazabicyclo[3.1.1]hept-3-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]-pyridazine;2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-7-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;{4-[2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo-[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;2-(4-Fluorophenyl)-3-(2-methoxypyrid-4-yl)-6-(5-methylhexahydropyrrolo[3,4-c]-pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-b]pyridazine;{4-[2-(4-Fluorophenyl)-8-methyl-6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]-pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;{4-[2-(4-Fluorophenyl)-7-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;(±)-2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(+)-2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(−)-2-(4-Fluorophenyl)-6-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(±)-{4-[2-(4-Fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)imidazo[1,2-b]-pyridazin-3-yl]pyrid-2-yl}methylamine;6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]-pyridazine;3-(2-Methylpyrid-4-yl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenylimidazo[1,2-b]pyridazine;3-(2-Methylpyrid-4-yl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-8-methyl-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-7-methyl-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-7-methyl-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-(2-methylpyrid-4-yl)-6-(4aS,7aS)-octahydropyrrolo[3,4-b]-pyrid-6-ylimidazo[1,2-b]pyridazine;{4-[2-(4-Fluorophenyl)-6-(octahydropyrrolo[3,4-b]pyrid-6-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;6-(4aR,7aR)-Octahydropyrrolo[3,4-b]pyrid-6-yl-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-3-(2-methylpyrid-4-yl)-6-(4aR,7aR)-octahydropyrrolo[3,4-b]-pyrid-6-ylimidazo[1,2-b]pyridazine;2-(4-Fluorophenyl)-8-methyl-6-(4aR,7aR)-octahydropyrrolo[3,4-b]pyrid-6-yl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(2,7-Diazaspiro[4.4]non-2-yl)-2-(4-fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine;6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]-pyridazine;(±)-2-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,8-diazaspiro[5.5]undecane;9-[2-(4-Fluorophenyl)-8-methyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;{4-[6-(2,9-Diazaspiro[5.5]undec-9-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;9-[2-(3,4-Difluorophenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;9-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;2-(3-Fluorophenyl)-3-pyrid-4-yl-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]-pyridazine;{4-[2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperid-1-yl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}methylamine;2-(4-Fluorophenyl)-6-[4-((R)-3-fluoropyrrolidin-1-yl)piperid-1-yl]-3-pyrid-4-ylimidazo[1,2-b]pyridazine;(R)-1-[1-(2-Phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl)piperid-4-yl]pyrrolidin-3-ol;and(R)-1-{1-[2-(3-Fluoro-5-methylphenyl)-3-pyrid-4-ylimidazo[1,2-b]pyridazin-6-yl]-piperid-4-yl}-pyrrolidin-3-ol;or a pharmaceutically acceptable salt of said compound.
 8. The method asclaimed in claim 6, wherein: R₂ represents a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen atoms and the groups C₁₋₆ alkyl, C₁₋₆ alkyloxy andC₁₋₆ fluoroalkyl.
 9. The method as claimed in claim 8, wherein: R₃represents a group selected from the group consisting of a hydrogen atomand a group C₁₋₃ alkyl, C₁₋₄ alkyloxy and —NR₄R₅, and wherein R₄ and R₅represent a hydrogen atom or a group C₁₋₄-alkyl.
 10. The method asclaimed in claim 9, wherein: R₃ represents a group selected from thegroup consisting of a hydrogen atom and a methyl and methoxy group. 11.The method as claimed in claim 9, wherein: R₃ represents a groupselected from the group consisting of —NH₂ and dimethylamino.
 12. Themethod as claimed in claim 6, wherein: R₇ and R₈ represent,independently of each other, a hydrogen atom or a methyl group.
 13. Themethod as claimed in claim 6, wherein: A represents a groupC₁₋₇-alkylene; B represents a group C₁₋₇-alkylene; L represents a carbonsubstituted with a group R_(e1) and a group R_(d); wherein R_(d)represents a hydrogen atom; and R_(d) represents a group NR₄R₅, in whichR₄ and R₅ represent, independently of each other, a group C₁₋₄-alkyl; oralternatively R_(e1) represents a pyrrolidinyl, morpholinyl,dimethylmorpholinyl, fluoropyrrolidinyl or hydroxypyrrolidinyl.
 14. Themethod as claimed in claim 6, wherein: A represents a groupC₁₋₇-alkylene optionally substituted with one or two groups R_(a); Brepresents a group C₁₋₇-alkylene optionally substituted with a groupR_(b); L represents a nitrogen atom substituted with a group R_(c) orR_(d); the carbon atoms of A and B being optionally substituted with oneor more groups R_(f), which may be identical to or different than eachother; two groups R_(a) may together form a group C₁₋₆-alkylene; R_(a)and R_(b) may together form a bond or a group C₁₋₆-alkylene; R_(a) andR_(c) may together form a bond or a group C₁₋₆-alkylene; R_(b) and R_(c)may together form a bond or a group C₁₋₆-alkylene; R_(d) represents asubstituent selected from the group consisting of C₁₋₆-alkyl,C₃₋₇-cycloalkyl, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,C₁₋₆-fluoroalkyl, benzyl and C₁-C₆-alkyl-C(O); and R_(f) represents agroup C₁₋₆-alkyl.
 15. The method as claimed in claim 6, wherein: Arepresents a group C₁₋₇-alkylene; B represents a group C₁₋₇-alkylene; Lrepresents a carbon atom substituted with two groups R_(e2); the carbonatoms of A and B being optionally substituted with one or more groupsR_(f), which may be identical to or different than each other; twogroups R_(e2) form, with the carbon atom that bears them, a pyrrolidine,piperidine, or morpholine group; and R_(f) represents a groupC₁₋₆-alkyl.
 16. The method as claimed in claim 6, wherein: R₂ representsa phenyl group optionally substituted with one or more substituentsselected from the group consisting of fluorine and chlorine atoms andthe methyl group; R₃ represents a hydrogen atom; the cyclic amine formedby —N-A-L-B— represents (±)-3-dimethylaminopyrrolidin-1-yl,4-(pyrrolidin-1-yl)piperid-1-yl, 4-(morpholin-4-yl)piperid-1-yl,4-(2,6-dimethylmorpholin-4-yl)piperid-1-yl, 4-dimethylaminopiperid-1-yl,4-(3-hydroxypyrrolidin-1-yl)piperid-1-yl, and4-(-3-fluoropyrrolidin-1-yl)piperid-1-yl; and R₇ and R₈ represent ahydrogen atom.
 17. The method as claimed in claim 6, wherein: R₂represents a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of fluorine and chlorineatoms and methyl, methoxy and trifluoromethyl groups; R₃ represents ahydrogen atom or a methyl, methoxy, —NH₂, methylamino or dimethylaminogroup; the cyclic amine formed by —N-A-L-B— represents a piperazin-1-yl,3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,3,3-dimethylpiperazin1-yl, 3,4-dimethylpiperazin-1-yl,cis-3,5-dimethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-(2-methoxyethyl)piperazin-1-yl, 4-(2-fluoroethyl)piperazin-1-yl,4-(2,2,2-trifluoroethyl)piperazin-1-yl, cyclopropylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl,4-n-butylpiperazin-1-yl, 4-(3-hydroxy-3-methylbutyl)piperazin-1-yl,4-cyclohexylpiperazin-1-yl, 4-acetylpiperazin-1-yl,4-isobutyrylpiperazin-1-yl, (±)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,(S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl,(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,(1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl,(1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl,5-isopropyl-2,5-diaza[2.2.1]hept-2-yl, 4-methyl[1.4]diazepan-1-yl,(±)-octahydropyrrolo[1,2-d][1.4]diazepin-2-yl,1,4-diazabicyclo[3.3.2]non-4-yl, (±)-3,6-diazabicyclo[3.2.0]hept-3-yl,hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,octahydro-6H-pyrrolo[3,4-b]pyrid-6-yl or(±)-(cis)-decahydro[2.6]naphthyridin-2-yl, 3-ethylpiperazin-1-yl,3,3-diethylpiperazin-1-yl, 3-fluoromethylpiperazin-1-yl,4-(3-hydroxymethyl)piperazin-1-yl,3-(1-hydroxy-1-methylethyl)piperazin-1-yl, 3-isopropylpiperazin-1-yl,(1R,5R)-3,6-diazabicyclo[3.2.0]hept-2-yl,5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl,1-((1S,4S)-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpropan-2-ol,3,6-diazabicyclo[3.1.1]hept-3-yl,5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(±)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(+)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(−)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(4aS,7aS)-octahydropyrrolo[3,4-b]pyrid-6-yl, or6,9-diazaspiro[4.5]dec-9-yl; and R₇ and R₈ represent, independently ofeach other, a hydrogen atom or a methyl group.
 18. The method as claimedin claim 6, wherein: R₂ represents a phenyl group optionally substitutedwith one or more substituents selected from the group consisting offluorine and chlorine atoms; R₃ represents a hydrogen atom or a methyl,methoxy or —NH₂ group; the cyclic amine formed by —N-A-L-B— represents a(±)-2,7-diazaspiro[4.4]non-2-yl, (±)-2,8-diazaspiro[4.5]dec-2-yl,(±)-2,7-diazaspiro[4.5]dec-2-yl, (±)-2,8-diazaspiro[4.5]dec-8-yl,(±)-2,7-diazaspiro[4.5]dec-7-yl, 3,9-diazaspiro[5.5]undec-3-yl,2,9-diazaspiro[5.5]undec-9-yl, (±)-2,8-diazaspiro[5.5]undec-2-yl or1-oxa-4,9-diazaspiro[5.5]undec-9-yl; and R₇ and R₈ represent a hydrogenatom.
 19. The method as claimed in claim 6 wherein the circadian rhythmdisorder is a sleep disorder related to the circadian rhythm in apatient comprising administering to said patient a therapeuticallyeffective amount of the compound of formula I.